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| {{for|the biotechnology company|Bio-Synthesis, Inc.}}
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| '''Biosynthesis''' (also called '''biogenesis''' or '''anabolism''') is a multi-step, [[catalyst|enzyme-catalyzed]] process where [[substrate (chemistry)|substrates]] are converted into more complex [[Product (chemistry)|products]]. In biosynthesis, simple [[Chemical compound|compound]]s are modified, converted into other compounds, or joined together to form [[macromolecules]]. This process often consists of [[metabolic pathway]]s. Some of these biosynthetic pathways are located within a single cellular [[organelle]], while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of [[lipid membrane]] components and [[nucleotide]]s.
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| The prerequisite elements for biosynthesis include: [[Precursor (chemistry)|precursor]] compounds, [[chemical energy]] (e.g. [[adenosine triphosphate|ATP]]), and catalytic [[enzymes]] which may require [[coenzymes]] (e.g.[[NADH]], [[NADPH]]). These elements create [[monomers]], the building blocks for macromolecules. Some important biological macromolecules include: [[proteins]], which are composed of [[amino acid]] monomers joined via [[peptide bonds]], and [[DNA]] molecules, which are composed of nucleotides joined via [[phosphodiester bonds]].
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| {{-}}
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| ==Properties of chemical reactions==
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| Biosynthesis occurs due to a series of chemical reactions. For these reactions to take place, the following elements are necessary:<ref name=isbn0-8153-3218-1 />
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| * [[Precursor (chemistry)|Precursor compounds]]: these compounds are the starting molecules or [[Substrate (biochemistry)|substrates]] in a reaction. These may also be viewed as the [[reactants]] in a given chemical process.
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| * [[Chemical energy]]: chemical energy can be found in the form of high energy molecules. These molecules are required for energetically unfavorable reactions. Furthermore, the [[hydrolysis]] of these compounds drives a reaction forward. High energy molecules, such as [[adenosine triphosphate|ATP]], have three [[phosphates]]. Often, the terminal phosphate is split off during hydrolysis and transferred to another molecule.
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| * [[Catalysis|Catalytic enzymes]]: these molecules are special [[proteins]] that catalyze a reaction by increasing the [[Reaction rate|rate of the reaction]] and lowering the [[Energy of activation|activation energy]].
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| * [[Coenzymes]] or [[Cofactor (biochemistry)|cofactors]]: cofactors are molecules that assist in chemical reactions. These may be [[metal ions]], vitamin derivatives such as [[NADH]] and [[Acetyl-CoA|acetyl CoA]], or non-vitamin derivatives such as ATP. In the case of NADH, the molecule transfers a hydrogen, whereas acetyl CoA transfers an [[acetyl group]], and ATP transfers a phosphate.
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| In the simplest sense, the reactions that occur in biosynthesis have the following format:<ref name=Zumdahl>{{cite book|last=Zumdahl|first=Steven S. Zumdahl, Susan A.|title=Chemistry|year=2008|publisher=Cengage Learning|location=CA|isbn=978-0547125329|edition=8th ed.}}</ref>
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| ::<math> Reactant \xrightarrow[enzyme]{} Product </math>
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| <br />
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| Some variations of this basic equation which will be discussed later in more detail are:<ref name=Voet>{{cite book|last=Pratt|first=Donald Voet, Judith G. Voet, Charlotte W.|title=Fundamentals of biochemistry : life at the molecular level|publisher=Wiley|location=Hoboken, NJ|isbn=978-0470547847|edition=4th ed.}}</ref>
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| 1. Simple compounds which are converted into other compounds, usually as part of a multiple step reaction pathway. Two examples of this type of reaction occur during the formation of [[nucleic acid]]s and the [[Aminoacyl tRNA synthetase|charging]] of [[tRNA]] prior to [[Translation (biology)|translation]]. For some of these steps, chemical energy is required:
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| <br />
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| ::<math> Precursor~molecule + ATP \rightleftharpoons {} product~AMP + PP_i</math>
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| <br />
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| 2. Simple compounds that are converted into other compounds with the assistance of cofactors. For example, the synthesis of [[phospholipid]]s requires acetyl CoA, while the synthesis of another membrane component, [[Sphingolipid|shingolipids]], requires NADH and FADH for the formation the [[sphingosine]] backbone. The general equation for these examples is:
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| <br />
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| ::<math> Precursor~molecule + Cofactor\xrightarrow[enzyme]{} macromolecule </math>
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| <br />
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| 3. Simple compounds that join together to create a macromolecule. For example, [[fatty acid]]s join together to form phopspholipids. In turn, phospholipids and [[cholesterol]] interact [[Noncovalent bonding|noncovalently]] in order to form the [[lipid bilayer]]. This reaction may be depicted as follows:
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| <br />
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| ::<math> Molecule~1+ Molecule~2 \xrightarrow{} macromolecule </math>
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| {{-}}
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| ==Membrane lipids==
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| [[File:The lipid and lipid bilayer.png|270x260px|thumbnail|left|Lipid membrane bilayer]]
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| Many intricate macromolecules are synthesized in a pattern of simple, repeated structures.<ref name="Molecular Cell Biology">{{cite book|last=Lodish|first=Harvey et al|title=Molecular cell biology|year=2007|publisher=W.H. Freeman|location=New York|isbn=978-0716743668|edition=6th ed.}}</ref> For example, the simplest structures of lipids are [[fatty acids]]. Fatty acids are [[hydrocarbon]] derivatives; they contain a [[carboxyl group]] “head” and a hydrocarbon chain “tail.”<ref name="Molecular Cell Biology" /> These fatty acids create larger components, which in turn incorporate noncovalent interactions to form the lipid bilayer.<ref name="Molecular Cell Biology" />
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| Fatty acid chains are found in two major components of membrane lipids: [[phospholipids]] and [[sphingolipids]]. A third major membrane component, [[cholesterol]], does not contain these fatty acid units.<ref name=Lehninger>{{cite book|last=Cox|first=David L. Nelson, Michael M.|title=Lehninger principles of biochemistry|year=2008|publisher=W.H. Freeman|location=New York|isbn=9780716771081|edition=5th ed.}}</ref>
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| ===Phospholipids===
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| The foundation of all biomembranes consists of a [[bilayer]] structure of phospholipids.<ref name=Hanin>{{cite book|last=Hanin|first=Israel|title=Phospholipids: Biochemical, Pharmaceutical, and Analytical Considerations|year=2013|publisher=Springer|isbn=1475713665}}</ref> The phospholipid molecule is [[amphipathic]]; it contains a [[hydrophilic]] polar head and a [[hydrophobic]] nonpolar tail.<ref name="Molecular Cell Biology" /> The phospholipid heads interact with each other and aqueous media, while the hydrocarbon tails orient themselves in the center, away from water.<ref name=Vance /> These latter interactions drive the bilayer structure that acts as a barrier for ions and molecules.<ref name=Katsaras>{{cite book|last=Katsaras et al|first=J.|title=Lipid bilayers : structure and interactions ; with 6 tables|year=2001|publisher=Springer|location=Berlin [u.a.]|isbn=978-3540675556}}</ref>
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| There are various types of phospholipids; consequently, their synthesis pathways differ. However, the first step in phospholipid synthesis involves the formation of [[phosphatidate]] or diacylglycerol 3-phosphate at the [[endoplasmic reticulum]] and [[outer mitochondrial membrane]].<ref name=Vance /> The synthesis pathway is found below:
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| [[File:Phosphatidic acid synthesis gif 2980x900.gif|700x200px|frameless|center| Phosphatidic acid synthesis]]
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| The pathway starts with glycerol 3-phosphate, which gets converted to lysophosphatidate via the addition of a fatty acid chain provided by [[Acyl coenzyme a|acyl coenzyme A]].<ref name="Stryer">{{cite book|last=Stryer|first=Jeremy M. Berg; John L. Tymoczko; Lubert|title=Biochemistry|year=2007|publisher=Freeman|location=New York|isbn=978-0716787242|edition=6. ed., 3. print.}}</ref> Then, lysophosphatidate is converted to phosphatidate via the addition of another fatty acid chain contributed by a second acyl CoA; all of these steps are catalyzed by the glycerol phosphate [[acyltransferase]] enzyme.<ref name=Stryer /> Phospholipid synthesis continues in the endoplasmic reticulum, and the biosynthesis pathway diverges depending on the components of the particular phospholipid.<ref name=Stryer />
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| ===Sphingolipids===
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| Like phospholipids, these fatty acid derivatives have a polar head and nonpolar tails.<ref name=Lehninger /> Unlike phospholipids, sphingolipids have a [[sphingosine]] backbone.<ref>{{cite journal|last=Gault|first=CR|coauthors=LM Obeid, YA Hannun|title=An Overview of sphingolipid metabolism: from synthesis to breakdown|journal=Adv Exp Med Biol|year=2010|volume=688|pages=1–23|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069696/pdf/nihms-283686.pdf}}</ref> Sphingolipids exist in [[eukaryotic]] cells and are particularly abundant in the [[central nervous system]].<ref name=Vance /> For example, sphingomyelin is part of the [[myelin sheath]] of nerve fibers.<ref name=Siegel />
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| Sphingolipids are formed from [[ceramide]]s that consist of a fatty acid chain attached to the amino group of a sphingosine backbone. These ceramides are synthesized from the [[acylation]] of sphingosine.<ref name=Siegel>{{cite book|last=Siegel|first=George J.|title=Basic neurochemistry : molecular, cellular and medical aspects|year=1999|publisher=Lippincott Williams & Wilkins|location=Philadelphia, Pa. [u.a.]|isbn=978-0397518203|edition=6. ed.}}</ref> The biosynthetic pathway for sphingosine is found below:
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| [[File:Sphingosine synthesis corrected.png|760x780px|frameless|center|Sphingosine synthesis]]
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| As the image denotes, during sphingosine synthesis, palmitoyl CoA and serine undergo a [[condensation reaction]] which results in the formation of dehydrosphingosine.<ref name=Vance /> This product is then reduced to form dihydrospingosine, which is converted to sphingosine via the [[oxidation reaction]] by [[FAD]].<ref name=Vance>{{cite book|last=Vance|first=Dennis E.|title=Biochemistry of lipids, lipoproteins and membranes|year=2008|publisher=Elsevier|location=Amsterdam|isbn=978-0444532190|edition=5th ed.|coauthors=Vance, Jean E.}}</ref>
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| ===Cholesterol===
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| This [[lipid]] belongs to a class of molecules called [[sterols]].<ref name=Lehninger /> Sterols have four fused rings and a [[hydroxyl group]].<ref name=Lehninger /> Cholesterol is a particularly important molecule. Not only does it serve as a component of lipid membranes, it is also a precursor to several [[steroid]] hormones, including [[cortisol]], [[testosterone]], and [[estrogen]].<ref name=Harris>{{cite book|last=Harris|first=J. Robin|title=Cholesterol binding and cholesterol transport proteins : structure and function in health and disease|year=2010|publisher=Springer|location=Dordrecht|isbn=978-9048186211}}</ref>
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| Cholesterol is synthesized from [[acetyl CoA]].<ref name=Harris /> The pathway is shown below:
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| [[File:HMG-CoA reductase pathway.png|346x450px|frameless|center|Cholesterol synthesis pathway]]
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| More generally, this synthesis occurs in three stages, with the first stage taking place in the [[cytoplasm]] and the second and third stages occurring in the endoplasmic reticulum.<ref name=Stryer /> The stages are as follows:<ref name=Harris />
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| ::1. The synthesis of [[isopentenyl pyrophosphate]], the “building block” of cholesterol
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| ::2. The formation of [[squalene]] via the condensation of six molecules of isopentenyl phosphate
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| ::3. The conversion of squalene into cholesterol via several enzymatic reactions
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| {{-}}
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| ==Nucleotides==
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| The biosynthesis of [[nucleotides]] involves enzyme-[[Catalyst|catalyzed]] reactions that convert substrates into more complex products.<ref name="isbn0-8153-3218-1">{{cite book | author = Alberts, Bruce | title = Molecular biology of the cell | publisher = Garland Science | location = New York | year = 2007 | pages = | isbn = 978-0815341055 | oclc = | doi = | accessdate = }}</ref> Nucleotides are the building blocks of [[DNA]] and [[RNA]]. Nucleotides are composed of a five-membered ring formed from [[ribose]] sugar in RNA, and [[deoxyribose]] sugar in DNA; these sugars are linked to a [[purine]] or [[pyrimidine]] base with a [[glycosidic bond]] and a [[phosphate]] group at the [[Ribonucleotide|5’ location]] of the sugar.<ref name="Watson's Molecular Biology of the Gene" />
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| ===Purine nucleotides===
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| [[Image:Nucleotides syn1.png|thumb|float|380x400px|<div style="border-width: 0px; border-bottom: 1px solid black; text-align: left;">'''The synthesis of IMP'''.</div></span>]]
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| The DNA nucleotides [[adenosine]] and [[guanosine]] consist of a purine base attached to a ribose sugar with a glycosidic bond. In the case of RNA nucleotides [[deoxyadenosine]] and [[deoxyguanosine]], the purine bases are attached to a deoxyribose sugar with a glycosidic bond. The purine bases on DNA and RNA nucleotides are synthesized in a twelve-step reaction mechanism present in most single-celled organisms. Higher [[eukaryotes]] employ a similar [[reaction mechanism]] in ten reaction steps. Purine bases are synthesized by converting [[phosphoribosyl pyrophosphate]] (PRPP) to [[inosine monophosphate]] (IMP), which is the first key intermediate in purine base biosynthesis.<ref name=Kappock/Purine>{{cite journal|last=Kappock|first=TJ|coauthors=Ealick, SE; Stubbe, J|title=Modular evolution of the purine biosynthetic pathway.|journal=Current Opinion in Chemical Biology|date=October 2000|volume=4|issue=5|pages=567–72|pmid=11006546}}</ref> Further enzymatic modification of [[Inosine monophosphate|IMP]] produces the adenosine and guanosine bases of nucleotides.
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| # The first step in purine biosynthesis is a [[condensation reaction]], performed by [[amidophosphoribosyltransferase|glutamine-PRPP amidotransferase]]. This enzyme transfers the [[amino group]] from [[glutamine]] to PRPP, forming [[5-phosphoribosylamine]]. The following step requires the activation of [[glycine]] by the addition of a [[phosphate]] group from [[adenosine triphosphate|ATP]].
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| # GAR synthetase<ref>{{cite journal|last=Sampei|first=G|coauthors=Baba, S; Kanagawa, M; Yanai, H; Ishii, T; Kawai, H; Fukai, Y; Ebihara, A; Nakagawa, N; Kawai, G|title=Crystal structures of glycinamide ribonucleotide synthetase, PurD, from thermophilic eubacteria.|journal=Journal of biochemistry|date=October 2010|volume=148|issue=4|pages=429–38|pmid=20716513|accessdate=26 November 2013}}</ref> performs the condensation of activated glycine onto PRPP, forming [[glycineamide ribonucleotide]] (GAR).
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| # [[GAR transformylase]] adds a [[formyl group]] onto the amino group of GAR, forming formylglycinamide ribonucleotide (FGAR).
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| # FGAR amidotransferase<ref>{{cite journal|last=Hoskins|first=AA|coauthors=Anand, R; Ealick, SE; Stubbe, J|title=The formylglycinamide ribonucleotide amidotransferase complex from Bacillus subtilis: metabolite-mediated complex formation.|journal=Biochemistry|date=Aug 17, 2004|volume=43|issue=32|pages=10314–27|pmid=15301530|accessdate=26 November 2013}}</ref> catalyzes the addition of a nitrogen group to FGAR, forming formylglycinamidine ribonucleotide (FGAM).
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| # [[AIR synthetase (FGAM cyclase)|FGAM cyclase]] catalyzes ring closure, which involves removal of a water molecule, forming the 5-membered [[imidazole]] ring [[5-Aminoimidazole ribotide|5-aminoimidazole ribonucleotide]] (AIR).
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| # N5-CAIR synthetase transfers a [[carboxyl]] group, forming the intermediate N5-carboxyaminoimidazole ribonucleotide (N5-CAIR).<ref>{{cite journal|last=Mueller|first=EJ|coauthors=Meyer, E; Rudolph, J; Davisson, VJ; Stubbe, J|title=N5-carboxyaminoimidazole ribonucleotide: evidence for a new intermediate and two new enzymatic activities in the de novo purine biosynthetic pathway of Escherichia coli.|journal=Biochemistry|date=Mar 1, 1994|volume=33|issue=8|pages=2269–78|pmid=8117684|accessdate=26 November 2013}}</ref>
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| # [[5-(carboxyamino)imidazole ribonucleotide mutase|N5-CAIR mutase]] rearranges the carboxyl functional group and transfers it onto the imidazole ring, forming [[5'-phosphoribosyl-4-carboxy-5-aminoimidazole|carboxyamino- imidazole ribonucleotide]] (CAIR). The two step mechanism of CAIR formation from AIR is mostly found in single celled organisms. Higher eukaryotes contain the enzyme AIR carboxylase,<ref>{{cite journal|last=Firestine|first=SM|coauthors=Poon, SW; Mueller, EJ; Stubbe, J; Davisson, VJ|title=Reactions catalyzed by 5-aminoimidazole ribonucleotide carboxylases from Escherichia coli and Gallus gallus: a case for divergent catalytic mechanisms.|journal=Biochemistry|date=Oct 4, 1994|volume=33|issue=39|pages=11927–34|pmid=7918411|accessdate=26 November 2013}}</ref> which transfers a carboxyl group directly to AIR imidazole ring, forming CAIR.
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| # [[Phosphoribosylaminoimidazolesuccinocarboxamide synthase|SAICAR synthetase]] forms a [[peptide bond]] between [[aspartate]] and the added carboxyl group of the imidazole ring, forming [[phosphoribosylaminoimidazolesuccinocarboxamide|N-succinyl-5-aminoimidazole-4-carboxamide ribonucleotide]] (SAICAR).
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| # [[Adenylosuccinate lyase|SAICAR lyase]] removes the carbon skeleton of the added aspartate, leaving the amino group and forming [[AICA ribonucleotide|5-aminoimidazole-4-carboxamide ribonucleotide]] (AICAR).
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| # [[AICAR transformylase]] transfers a carbonyl group to AICAR, forming [[5-Formamidoimidazole-4-carboxamide ribotide|N-formylaminoimidazole- 4-carboxamide ribonucleotide]] (FAICAR).
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| # The final step involves the enzyme [[inosine monophosphate synthase|IMP synthase]], which performs the purine ring closure and forms the [[inosine monophosphate]] (IMP) intermediate.<ref name=Lehninger />
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| ===Pyrimidine nucleotides===
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| [[File:Nucleotides syn2.png|310x290px|frame|right|Uridine monophosphate (UMP) biosynthesis]]
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| Other DNA and RNA nucleotide bases that are linked to the ribose sugar via a glycosidic bond are [[thymine]], [[cytosine]] and [[uracil]] (which is only found in RNA).
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| [[Uridine monophosphate]] biosynthesis involves an enzyme that is located in the [[Inner mitochondrial membrane|mitochondrial inner membrane]] and multifunctional enzymes that are located in the [[cytosol]].<ref name="Srere/Metabolic enzymes">{{cite journal|last=Srere|first=PA|title=Complexes of sequential metabolic enzymes.|journal=Annual review of biochemistry|year=1987|volume=56|pages=89–124|pmid=2441660}}</ref>
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| # The first step involves the enzyme [[carbamoyl phosphate synthase]] combining [[glutamine]] with [[CO2|CO<sub>2</sub>]] in an ATP dependent reaction to form [[carbamoyl phosphate]].
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| # [[Aspartate carbamoyltransferase]] [[Condensation reaction|condenses]] carbamoyl phosphate with aspartate to form uridosuccinate.
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| # [[Dihydroorotase]] performs [[Ring-closure reaction|ring closure]], a reaction that loses water, to form [[dihydroorotate]].
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| # [[Dihydroorotate dehydrogenase]], located within the mitochondrial inner membrane,<ref name="Srere/Metabolic enzymes" /> oxidizes dihydroorotate to [[orotate]].
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| # Orotate phosphoribosyl hydrolase (OMP pyrophosphorylase) condenses orotate with [[PRPP]] to form [[orotidine 5'-monophosphate|orotidine-5’-phosphate]].
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| # [[OMP decarboxylase]] catalyzes the conversion of orotidine-5’-phosphate to [[Uridine monophosphate|UMP]].<ref name="Broach/Yeast nucleotide">{{cite book|last=Broach|first=edited by Jeffrey N. Strathern, Elizabeth W. Jones, James R.|title=The Molecular biology of the yeast Saccharomyces|year=1981|publisher=Cold Spring Harbor Laboratory|location=Cold Spring Harbor, N.Y.|isbn=0879691395}}</ref>
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| After the uridine nucleotide base is synthesized, the other bases, cytosine and thymine are synthesized. Cytosine biosynthesis is a two-step reaction which involves the conversion of UMP to [[Uridine triphosphate|UTP]]. [[Phosphate]] addition to UMP is catalyzed by a [[kinase]] enzyme. The enzyme [[CTP synthase]] catalyzes the next reaction step: the conversion of UTP to [[cytidine triphosphate|CTP]] by transferring an [[amino group]] from glutamine to uridine; this forms the cytosine base of CTP.<ref name="O'Donovan/ pyrimidine microorg">{{cite journal|last=O'Donovan|first=GA|coauthors=Neuhard, J|title=Pyrimidine metabolism in microorganisms.|journal=Bacteriological reviews|date=September 1970|volume=34|issue=3|pages=278–343|pmid=4919542}}</ref> The mechanism, which depicts the reaction UTP + ATP + glutamine ⇔ CTP + ADP + glutamate, is below:
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| [[File:Thymidylate synthase reaction.svg|410x250px|frameless|right|'Thymidylate synthase reaction: dUMP + 5,10-methylenetetrahydrofolate ⇔ dTMP + dihydrofolate]]
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| [[File:Ctp synthase mechanism.jpg|480x250px|frameless|center|Ctp synthase mechanism: UTP + ATP + glutamine ⇔ CTP + ADP + glutamate]]
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| Cytosine is a nucleotide that is present in both DNA and RNA. However, uracil is only found in RNA. Therefore, after UTP is synthesized, it is must be converted into a [[deoxy]] form to be incorporated into DNA. This conversion involves the enzyme [[Ribonucleoside-triphosphate reductase|ribonucleoside triphosphate reductase]]. This reaction that removes the 2’-OH of the ribose sugar to generate deoxyribose is not affected by the bases attached to the sugar. This non-specificity allows ribonucleoside triphosphate reductase to convert all [[nucleotide triphosphates]] to [[deoxyribonucleotide]] by a similar mechanism.<ref name="O'Donovan/ pyrimidine microorg" />
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| In contrast to uracil, thymine bases are found mostly in DNA, not RNA. Cells do not normally contain thymine bases that are linked to ribose sugars in RNA, thus indicating that cells only synthesize deoxyribose-linked thymine. The enzyme [[thymidylate synthetase]] is responsible for synthesizing thymine residues from [[dUMP]] to [[dTMP]]. This reaction transfers a [[methyl]] group onto the uracil base of dUMP to generate dTMP.<ref name="O'Donovan/ pyrimidine microorg" /> The thymidylate synthase reaction, dUMP + 5,10-methylenetetrahydrofolate ⇔ dTMP + dihydrofolate, is shown to the right.
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| {{-}}
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| ==DNA==
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| [[File:DNA replication en.svg|240x250px|framed|right|As DNA polymerase moves in a 3’ to 5’ direction along the template strand, it synthesizes a new strand in the 5’ to 3’ direction]]
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| Although there are differences between [[eukaryotic]] and [[prokaryotic]] DNA synthesis, the following section denotes key characteristics of DNA replication shared by both organisms.
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| [[DNA]] is composed of [[nucleotide]]s that are joined by [[phosphodiester bonds]].<ref name="Molecular Cell Biology" /> [[DNA replication|DNA synthesis]], which takes place in the [[Cell nucleus|nucleus]], is a [[Semiconservative replication|semiconservative]] process, which means that the resulting DNA molecule contains an original strand from the parent structure and a new strand.<ref name="Karp's Cell and Molecular Biology">{{cite book|last=Geer|first=Gerald Karp ; responsible for the revision of chapter 15 Peter van der|title=Cell and molecular biology : concepts and experiments|year=2004|publisher=J. Wiley & Sons|location=New York|isbn=978-0471656654|edition=4th ed., Wiley International ed.}}</ref> DNA synthesis is catalyzed by a family of [[DNA polymerases]] that require four deoxynucleoside triphosphates, a [[Template strand#Elongation|template strand]], and a [[Rna primer|primer]] with a free 3’OH in which to incorporate nucleotides.<ref name=Griffiths>{{cite book|last=Griffiths|first=Anthony J. F.|title=Modern genetic analysis|year=1999|publisher=Freeman|location=New York|isbn=978-0716731184|edition=2. print.}}</ref>
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| In order for DNA replication to occur, a [[Replication fork#Replication fork|replication fork]] is created by enzymes called [[helicase]]s which unwind the DNA helix.<ref name=Griffiths /> [[Topoisomerase]]s at the replication fork remove [[DNA supercoil|supercoils]] caused by DNA unwinding, and [[Single-strand binding protein|single-stranded DNA binding proteins]] maintain the two single-stranded DNA templates stabilized prior to replication.<ref name="Watson's Molecular Biology of the Gene">{{cite book|last=Watson|first=James D. et al|title=Molecular biology of the gene|year=2007|publisher=Benjamin Cummings|location=San Francisco, Calif.|isbn=978-0805395921|edition=6th ed.}}</ref>
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| DNA synthesis is initiated by the [[RNA polymerase]] [[primase]], which makes an RNA primer with a free 3’OH.<ref name=Griffiths /> This primer is attached to the single-stranded DNA template, and DNA polymerase elongates the chain by incorporating nucleotides; DNA polymerase also proofreads the newly synthesized DNA strand.<ref name=Griffiths />
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| During the polymerization reaction catalyzed by DNA polymerase, a [[nucleophilic attack]] occurs by the 3’OH of the growing chain on the innermost phosphorus atom of a deoxynucleoside triphosphate; this yields the formation of a [[Phosphodiester bridges|phosphodiester bridge]] that attaches a new nucleotide and releases [[pyrophosphate]].<ref name=Stryer />
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| Two types of strands are created simultaneously during replication: the [[Leading strand#Replication fork|leading strand]], which is synthesized continuously and grows towards the replication fork, and the [[Lagging strand#Replication fork|lagging strand]], which is made discontinuously in [[Okazaki fragments]] and grows away from the replication fork.<ref name="Karp's Cell and Molecular Biology" /> Okazaki fragments are [[covalently]] joined by [[DNA ligase]] to form a continuous strand.<ref name="Karp's Cell and Molecular Biology" />
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| Then, to complete DNA replication, RNA primers are removed, and the resulting gaps are replaced with DNA and joined via DNA ligase.<ref name="Karp's Cell and Molecular Biology" />
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| {{-}}
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| ==Amino acids==
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| A protein is a polymer that is composed from [[amino acids]] that are linked by [[peptide bonds]]. There are more than [[Amino acid#Non-standard amino acids|300 amino acids]] found in nature of which only twenty, known as the [[Amino acid#Standard amino acids|standard amino acids]], are the building blocks for protein.<ref name="AA structure">{{cite journal|last=Wu|first=G|title=Amino acids: metabolism, functions, and nutrition.|journal=Amino acids|date=May 2009|volume=37|issue=1|pages=1–17|pmid=19301095|accessdate=26 November 2013}}</ref> Only [[green plants]] and most [[microbes]] are able to [[synthesize]] all of the 20 standard amino acids that are needed by all living species. [[Mammals]] can only synthesize ten of the twenty standard amino acids. The other amino acids, [[valine]], [[methionine]], [[leucine]], [[isoleucine]], [[phenylalanine]], [[lysine]], [[threonine]] and [[tryptophan]] for adults and [[histidine]], and [[arginine]] for babies are obtained through diet.<ref>{{cite journal|last=Mousdale|first=D. M.|coauthors=Coggins, J. R.|title=Amino Acid Synthesis|journal=Target Sites for Herbicide Action|year=1991|pages=29–56|url=http://link.springer.com/chapter/10.1007/978-1-4899-2433-9_2|accessdate=26 November 2013}}</ref>
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| ===Amino acid basic structure===
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| [[File:L-amino acid general.svg|left|190x70px|frame|L-amino acid]]The general structure of the standard amino acids includes a [[Amine|primary amino group]], a [[carboxyl group]] and the [[functional group]] attached to the [[Alpha-carbon|α-carbon]]. The different amino acids are identified by the functional group. As a result of the three different groups attached to the α-carbon, amino acids are [[Chirality (chemistry)#Symmetry|asymmetrical molecules]]. For all standard amino acids, except [[glycine]], the α-carbon is a [[chiral center]]. In the case of glycine, the α-carbon has two hydrogen atoms, thus adding symmetry to this molecule. With the exception of [[proline]], all of the amino acids found in life have the [[Chirality (chemistry)#By configuration: D- and L-|L-isoform]] conformation. Proline has a functional group on the α-carbon that forms a ring with the amino group.<ref name="AA structure" />
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| [[File:Glutamine oxoglutarate aminotransferase and Glutamine synthetase.svg|240x240px|frameless|right|Glutamine oxoglutarate aminotransferase and glutamine synthetase]]
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| ===Nitrogen source===
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| One major step in amino acid biosynthesis involves incorporating a nitrogen group onto the α-carbon. In cells, there are two major pathways of incorporating nitrogen groups. One pathway involves the enzyme [[glutamine oxoglutarate aminotransferase]] (GOGAT) which removes the [[amide]] amino group of [[glutamine]] and transfers it onto [[2-oxoglutarate]], producing two [[glutamate]] molecules. In this catalysis reaction, glutamine serves as the nitrogen source. An image illustrating this reaction is found to the right.
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| The other pathway for incorporating nitrogen onto the α-carbon of amino acids involves the enzyme [[glutamate dehydrogenase]] (GDH). GDH is able to transfer [[ammonia]] onto 2-oxoglutarate and form glutamate. Furthermore, the enzyme [[glutamine synthetase]] (GS) is able to transfer ammonia onto glutamate and synthesize glutamine, replenishing glutamine.<ref name="AA Metabolism Miflin">{{cite journal|last=Miflin|first=B. J.|coauthors=Lea, P. J.|title=Amino Acid Metabolism|journal=Annual Review of Plant Physiology|year=1977|pages=299–329|url=http://www.annualreviews.org/doi/pdf/10.1146/annurev.pp.28.060177.001503|accessdate=26 November 2013}}</ref>
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| ===The glutamate family of amino acids===
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| The [[glutamate]] family of amino acids includes the amino acids that derive from the amino acid glutamate. This family includes: glutamate, [[glutamine]], [[proline]], and [[arginine]]. This family also includes the amino acid [[lysine]], which is derived from [[α-ketoglutarate]].<ref name="Amino Families">{{cite journal|last=Umbarger|first=HE|title=Amino acid biosynthesis and its regulation.|journal=Annual review of biochemistry|year=1978|volume=47|pages=532–606|pmid=354503}}</ref>
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| The biosynthesis of glutamate and glutamine is a key step in the nitrogen assimilation discussed above. The enzymes [[GOGAT]] and [[Glutamate dehydrogenase|GDH]] catalyze the [[nitrogen assimilation]] reactions.
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| In bacteria, the enzyme [[glutamate 5-kinase]] initiates the biosynthesis of proline by transferring a phosphate group from ATP onto glutamate. The next reaction is catalyzed by the enzyme [[Glutamate-5-semialdehyde dehydrogenase|pyrroline-5-carboxylate synthase]] (P5CS), which catalyzes the reduction of the [[Gamma-carboxylation|ϒ-carboxyl]] group of L-glutamate 5-phosphate. This results in the formation of glutamate semialdehyde, which spontaneously cyclizes to pyrroline-5-carboxylate. Pyrroline-5-carboxylate is further reduced by the enzyme pyrroline-5-carboxylate reductase (P5CR) to yield a proline amino acid.<ref>{{cite journal|last=Pérez-Arellano|first=I|coauthors=Carmona-Alvarez, F; Martínez, AI; Rodríguez-Díaz, J; Cervera, J|title=Pyrroline-5-carboxylate synthase and proline biosynthesis: from osmotolerance to rare metabolic disease.|journal=Protein science : a publication of the Protein Society|date=March 2010|volume=19|issue=3|pages=372–82|pmid=20091669|accessdate=11 December 2013}}</ref>
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| In the first step of arginine biosynthesis in bacteria, glutamate is [[acetylated]] by transferring the acetyl group from acetyl-CoA at the N-α position; this prevents spontaneous cyclization. The enzyme [[N-acetylglutamate synthase]] (glutamate N-acetyltransferase) is responsible for catalyzing the acetylation step. Subsequent steps are catalyzed by the enzymes [[acetylglutamate kinase|N-acetylglutamate kinase]], [[N-acetyl-gamma-glutamyl-phosphate reductase]], and [[acetylornithine transaminase|acetylornithine/succinyldiamino pimelate aminotransferase]] and yield the N-acetyl-L-ornithine. The acetyl group of acetylornithine is removed by the enzyme [[Acetylornithine deacetylase|acetylornithinase]] (AO) or [[Glutamate N-acetyltransferase|ornithine acetyltransferase]] (OAT), and this yields [[ornithine]]. Then, the enzymes [[citrulline]] and [[argininosuccinate]] convert ornithine to arginine.<ref>{{cite journal|last=Xu|first=Y|coauthors=Labedan, B; Glansdorff, N|title=Surprising arginine biosynthesis: a reappraisal of the enzymology and evolution of the pathway in microorganisms.|journal=Microbiology and molecular biology reviews : MMBR|date=March 2007|volume=71|issue=1|pages=36–47|pmid=17347518}}</ref>
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| [[File:Lysine Biosynthesis.png|320x400px|right|framed|The diaminopimelic acid pathway]]
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| There are two distinct lysine biosynthetic pathways: the diaminopimelic acid pathway, and the [[Alpha-aminoadipate pathway|α-amionoadipate pathway]], which is not present in prokaryotes. The most common of the two synthetic pathways is the diaminopimelic acid pathway; it consists of several enzymatic reactions that add carbon groups to aspartate to yield lysine:<ref>{{cite journal|last=Xu|first=H|coauthors=Andi, B; Qian, J; West, AH; Cook, PF|title=The alpha-aminoadipate pathway for lysine biosynthesis in fungi.|journal=Cell biochemistry and biophysics|year=2006|volume=46|issue=1|pages=43–64|pmid=16943623}}</ref>
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| # [[Aspartate kinase]] initiates the diaminopimelic acid pathway by phosphorylating aspartate and producing aspartyl phosphate.
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| # [[Aspartate-semialdehyde dehydrogenase|Aspartate semialdehyde dehydrogenase]] catalyzes the [[NADPH]]-dependent reduction of aspartyl phosphate to yield aspartate semialdehyde.
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| # [[Dihydrodipicolinate synthase]] catalyzes the condensation reaction of pyruvate with aspartate semialdehyde to yield 2,3-dihydrodipicolinate.
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| # Dihydrodipicolinate reductase catalyzes the reduction of 2,3-dihydrodipicolinate by NADPH to yield Δ’-piperideine-2,6-dicarboxylate.
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| # [[Tetrahydrodipicolinate N-acetyltransferase|Tetrahydrodipicolinate acyltransferase]] catalyzes the acetylation reaction that results in ring opening and yields N-acetyl α-amion-ε-ketopimelate.
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| # [[Succinyldiaminopimelate transaminase|N-succinyl-α-amion-ε-ketopimelate-glutamate aminotransaminase]] catalyzes the transamination reaction that removes the keto group of N-acetyl α-amion-ε-ketopimelate and replaces it with an amino group to yield N-succinyl-L-diaminopimelate.<ref>{{cite journal|last=PETERKOFSKY|first=B|coauthors=GILVARG, C|title=N-Succinyl-L-diaminopimelic-glutamic transaminase.|journal=The Journal of biological chemistry|date=May 1961|volume=236|pages=1432–8|pmid=13734750}}</ref>
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| # [[succinyl-diaminopimelate desuccinylase|N-acyldiaminopimelate deacylase]] catalyzes the deacylation of N-succinyl-L-diaminopimelate to yield L,L-diaminopimelate.<ref>{{cite journal|last=KINDLER|first=SH|coauthors=GILVARG, C|title=N-Succinyl-L-2,6-diaminopimelic acid deacylase.|journal=The Journal of biological chemistry|date=December 1960|volume=235|pages=3532–5|pmid=13756049}}</ref>
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| # [[diaminopimelate epimerase|DAP epimerase]] catalyzes the conversion of L,L-diaminopimelate to the [[Meso form|meso]] form of L,L-diaminopimelate.<ref>{{cite journal|last=Born|first=TL|coauthors=Blanchard, JS|title=Structure/function studies on enzymes in the diaminopimelate pathway of bacterial cell wall biosynthesis.|journal=Current opinion in chemical biology|date=October 1999|volume=3|issue=5|pages=607–13|pmid=10508663}}</ref>
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| # [[Diaminopimelate decarboxylase|DAP decarboxylase]] catalyzes the removal of the carboxyl group, yielding L-lysine.
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| ===The serine family of amino acids===
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| The [[serine]] family of amino acid includes: serine, [[cysteine]], and [[glycine]]. Most microorganisms and plants obtain the sulfur for synthesizing [[methionine]] from the amino acid cysteine. Furthermore, the conversion of serine to glycine provides the carbons needed for the biosynthesis of the methionine and [[histidine]].<ref name="Amino Families" />
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| During serine biosynthesis,<ref>{{cite web|title=Escherichia coli K-12 substr. MG1655|url=http://ecocyc.org/ECOLI/NEW-IMAGE?type=PATHWAY&object=SERSYN-PWY&detail-level=4&detail-level=3|work=serine biosynthesis|publisher=SRI International|accessdate=12 December 2013}}</ref> the enzyme [[phosphoglycerate dehydrogenase]] catalyzes the initial reaction that [[oxidizes]] [[3-phospho-D-glycerate]] to yield [[Phosphohydroxypyruvic acid|3-phosphonooxypyruvate]].<ref>{{cite journal|last=Bell|first=JK|coauthors=Grant, GA; Banaszak, LJ|title=Multiconformational states in phosphoglycerate dehydrogenase.|journal=Biochemistry|date=Mar 30, 2004|volume=43|issue=12|pages=3450–8|pmid=15035616|accessdate=12 December 2013}}</ref> The following reaction is catalyzed by the enzyme [[phosphoserine aminotransferase]], which transfers an amino group from glutamate onto 3-phosphonooxypyruvate to yield [[Phosphoserine|L-phosphoserine]].<ref>{{cite journal|last=Dubnovitsky|first=AP|coauthors=Kapetaniou, EG; Papageorgiou, AC|title=Enzyme adaptation to alkaline pH: atomic resolution (1.08 A) structure of phosphoserine aminotransferase from Bacillus alcalophilus.|journal=Protein science : a publication of the Protein Society|date=January 2005|volume=14|issue=1|pages=97–110|pmid=15608117|accessdate=12 December 2013}}</ref> The final step is catalyzed by the enzyme [[phosphoserine phosphatase]], which [[Dephosphorylation|dephosphorylates]] L-phosphoserine to yield [[L-serine]].<ref>{{cite journal|last=Wang|first=W|coauthors=Kim, R; Jancarik, J; Yokota, H; Kim, SH|title=Crystal structure of phosphoserine phosphatase from Methanococcus jannaschii, a hyperthermophile, at 1.8 A resolution.|journal=Structure (London, England : 1993)|date=Jan 10, 2001|volume=9|issue=1|pages=65–71|pmid=11342136}}</ref>
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| There are two known pathways for the biosynthesis of glycine. Organisms that use [[ethanol]] and [[acetate]] as the major carbon source utilize the [[Glyconeogenesis|glyconeogenic]] pathway to synthesize [[glycine]]. The other pathway of glycine biosynthesis is known as the [[glycolytic]] pathway. This pathway converts serine synthesized from the intermediates of [[glycolysis]] to glycine. In the glycolytic pathway, the enzyme [[serine hydroxymethyltransferase]] catalyzes the cleavage of serine to yield glycine and transfers the cleaved carbon group of serine onto [[tetrahydrofolate]], forming [[5,10-Methylenetetrahydrofolate|5,10-methylene-tetrahydrofolate]].<ref>{{cite journal|last=Monschau|first=N|coauthors=Stahmann, KP; Sahm, H; McNeil, JB; Bognar, AL|title=Identification of Saccharomyces cerevisiae GLY1 as a threonine aldolase: a key enzyme in glycine biosynthesis.|journal=FEMS microbiology letters|date=May 1, 1997|volume=150|issue=1|pages=55–60|pmid=9163906}}</ref>
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| Cysteine biosynthesis is a two-step reaction that involves the incorporation of inorganic [[sulfur]]. In microorganisms and plants, the enzyme [[Serine O-acetyltransferase|serine acetyltransferase]] catalyzes the transfer of acetyl group from [[acetyl-CoA]] onto L-serine to yield [[O-acetyl-L-serine]].<ref>{{cite journal|last=Pye|first=VE|coauthors=Tingey, AP; Robson, RL; Moody, PC|title=The structure and mechanism of serine acetyltransferase from Escherichia coli.|journal=The Journal of biological chemistry|date=Sep 24, 2004|volume=279|issue=39|pages=40729–36|pmid=15231846|accessdate=12 December 2013}}</ref> The following reaction step, catalyzed by the enzyme [[Cysteine synthase|O-acetyl serine (thiol) lyase]], replaces the acetyl group of O-acetyl-L-serine with sulfide to yield cysteine.<ref>{{cite journal|last=Huang|first=B|coauthors=Vetting, MW; Roderick, SL|title=The active site of O-acetylserine sulfhydrylase is the anchor point for bienzyme complex formation with serine acetyltransferase.|journal=Journal of bacteriology|date=May 2005|volume=187|issue=9|pages=3201–5|pmid=15838047|accessdate=12 December 2013}}</ref>
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| ===The aspartate family of amino acids===
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| The [[aspartate]] family of amino acids includes: [[threonine]], [[lysine]], [[methionine]], [[isoleucine]], and aspartate. Lysine and isoleucine are considered part of the aspartate family even though part of their carbon skeleton is derived from [[pyruvate]]. In the case of methionine, the methyl carbon is derived from serine and the sulfur group, but in most organisms, it is derived from cysteine.<ref name="Amino Families" />
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| The biosynthesis of aspartate is a one step reaction that is catalyzed by a single enzyme. The enzyme [[aspartate aminotransferase]] catalyzes the transfer of an amino group from aspartate onto [[α-ketoglutarate]] to yield glutamate and [[oxaloacetate]].<ref>{{cite journal|last=McPhalen|first=CA|coauthors=Vincent, MG; Picot, D; Jansonius, JN; Lesk, AM; Chothia, C|title=Domain closure in mitochondrial aspartate aminotransferase.|journal=Journal of molecular biology|date=Sep 5, 1992|volume=227|issue=1|pages=197–213|pmid=1522585|accessdate=12 December 2013}}</ref> Asparagine is synthesized by an ATP-dependent addition of an amino group onto aspartate; [[asparagine synthetase]] catalyzes the addition of nitrogen from glutamine or soluble ammonia to aspartate to yield asparagine.<ref>{{cite journal|last=Larsen|first=TM|coauthors=Boehlein, SK; Schuster, SM; Richards, NG; Thoden, JB; Holden, HM; Rayment, I|title=Three-dimensional structure of Escherichia coli asparagine synthetase B: a short journey from substrate to product.|journal=Biochemistry|date=Dec 7, 1999|volume=38|issue=49|pages=16146–57|pmid=10587437|accessdate=12 December 2013}}</ref> [[File:Lysine Biosynthesis.png|thumb|framed|400x400px|The diaminopimelic acid lysine biosynthetic pathway]]
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| The diaminopimelic acid biosynthetic pathway of lysine belongs to the aspartate family of amino acids. This pathway involves nine enzyme-catalyzed reactions that convert aspartate to lysine.<ref name="Lysine pathways">{{cite journal|last=Velasco|first=AM|coauthors=Leguina, JI; Lazcano, A|title=Molecular evolution of the lysine biosynthetic pathways.|journal=Journal of molecular evolution|date=October 2002|volume=55|issue=4|pages=445–59|pmid=12355264}}</ref>
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| # [[Aspartate kinase]] catalyzes the initial step in the diaminopimelic acid pathway by transferring a [[phosphoryl]] from ATP onto the carboxylate group of aspartate, which yields aspartyl-β-phosphate.<ref>{{cite journal|last=Kotaka|first=M|coauthors=Ren, J; Lockyer, M; Hawkins, AR; Stammers, DK|title=Structures of R- and T-state Escherichia coli aspartokinase III. Mechanisms of the allosteric transition and inhibition by lysine.|journal=The Journal of biological chemistry|date=Oct 20, 2006|volume=281|issue=42|pages=31544–52|pmid=16905770|accessdate=12 December 2013}}</ref>
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| # [[Aspartate-semialdehyde dehydrogenase]] catalyzes the reduction reaction by [[dephosphorylation]] of aspartyl-β-phosphate to yield aspartate-β-semialdehyde.<ref>{{cite journal|last=Hadfield|first=A|coauthors=Kryger, G; Ouyang, J; Petsko, GA; Ringe, D; Viola, R|title=Structure of aspartate-beta-semialdehyde dehydrogenase from Escherichia coli, a key enzyme in the aspartate family of amino acid biosynthesis.|journal=Journal of molecular biology|date=Jun 18, 1999|volume=289|issue=4|pages=991–1002|pmid=10369777|accessdate=12 December 2013}}</ref>
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| # [[4-hydroxy-tetrahydrodipicolinate synthase|Dihydrodipicolinate synthase]] catalyzes the [[Condensation reaction|condensation]] reaction of aspartate-β-semialdehyde with pyruvate to yield dihydrodipicolinic acid.<ref>{{cite journal|last=Mirwaldt|first=C|coauthors=Korndörfer, I; Huber, R|title=The crystal structure of dihydrodipicolinate synthase from Escherichia coli at 2.5 A resolution.|journal=Journal of molecular biology|date=Feb 10, 1995|volume=246|issue=1|pages=227–39|pmid=7853400|accessdate=12 December 2013}}</ref>
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| # [[Dihydrodipicolinate reductase|4-hydroxy-tetrahydrodipicolinate reductase]] catalyzes the reduction of dihydrodipicolinic acid to yield tetrahydrodipicolinic acid.<ref>{{cite journal|last=Cirilli|first=M|coauthors=Zheng, R; Scapin, G; Blanchard, JS|title=The three-dimensional structures of the Mycobacterium tuberculosis dihydrodipicolinate reductase-NADH-2,6-PDC and -NADPH-2,6-PDC complexes. Structural and mutagenic analysis of relaxed nucleotide specificity.|journal=Biochemistry|date=Sep 16, 2003|volume=42|issue=36|pages=10644–50|pmid=12962488|accessdate=12 December 2013}}</ref>
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| # [[2,3,4,5-tetrahydropyridine-2,6-dicarboxylate N-succinyltransferase|Tetrahydrodipicolinate N-succinyltransferase]] catalyzes the transfer of a succinyl group from succinyl-CoA on to tetrahydrodipicolinic acid to yield N-succinyl-L-2,6-diaminoheptanedioate.<ref>{{cite journal|last=Beaman|first=TW|coauthors=Binder, DA; Blanchard, JS; Roderick, SL|title=Three-dimensional structure of tetrahydrodipicolinate N-succinyltransferase.|journal=Biochemistry|date=Jan 21, 1997|volume=36|issue=3|pages=489–94|pmid=9012664|accessdate=12 December 2013}}</ref>
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| # N-succinyldiaminopimelate aminotransferase catalyzes the transfer of an amino group from glutamate onto N-succinyl-L-2,6-diaminoheptanedioate to yield N-succinyl-L,L-diaminopimelic acid.<ref>{{cite journal|last=Weyand|first=S|coauthors=Kefala, G; Weiss, MS|title=The three-dimensional structure of N-succinyldiaminopimelate aminotransferase from Mycobacterium tuberculosis.|journal=Journal of molecular biology|date=Mar 30, 2007|volume=367|issue=3|pages=825–38|pmid=17292400|accessdate=12 December 2013}}</ref>
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| # [[Succinyldiaminopimelate transaminase|Succinyl-diaminopimelate desuccinylase]] catalyzes the removal of acyl group from N-succinyl-L,L-diaminopimelic acid to yield L,L-diaminopimelic acid.<ref>{{cite journal|last=Nocek|first=BP|coauthors=Gillner, DM; Fan, Y; Holz, RC; Joachimiak, A|title=Structural basis for catalysis by the mono- and dimetalated forms of the dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase.|journal=Journal of molecular biology|date=Apr 2, 2010|volume=397|issue=3|pages=617–26|pmid=20138056|accessdate=12 December 2013}}</ref>
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| # [[Diaminopimelate epimerase]] catalyzes the inversion of the α-carbon of L,L-diaminopimelic acid to yield [[meso-diaminopimelic acid]].<ref>{{cite journal|last=Pillai|first=B|coauthors=Cherney, M; Diaper, CM; Sutherland, A; Blanchard, JS; Vederas, JC; James, MN|title=Dynamics of catalysis revealed from the crystal structures of mutants of diaminopimelate epimerase.|journal=Biochemical and biophysical research communications|date=Nov 23, 2007|volume=363|issue=3|pages=547–53|pmid=17889830|accessdate=12 December 2013}}</ref>
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| # Siaminopimelate decarboxylase catalyzes the final step in lysine biosynthesis that removes the carbon dioxide group from meso-diaminopimelic acid to yield L-lysine.<ref>{{cite journal|last=Gokulan|first=K|coauthors=Rupp, B; Pavelka MS, Jr; Jacobs WR, Jr; Sacchettini, JC|title=Crystal structure of Mycobacterium tuberculosis diaminopimelate decarboxylase, an essential enzyme in bacterial lysine biosynthesis.|journal=The Journal of biological chemistry|date=May 16, 2003|volume=278|issue=20|pages=18588–96|pmid=12637582|accessdate=12 December 2013}}</ref>
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| {{-}}
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| ==Proteins==
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| [[File:Peptide syn.png|200x200px|framed|right|The tRNA anticodon interacts with the mRNA codon in order to bind an amino acid to growing polypeptide chain.]][[File:Charge tRNA.png|200x200px|framed|right|The process of tRNA charging]]
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| Protein synthesis occurs via a process called [[Translation (biology)|translation]].<ref name=Weaver>{{cite book|last=Weaver|first=Robert F.|title=Molecular biology|year=2005|publisher=McGraw-Hill Higher Education|location=Boston|isbn=0-07-284611-9|edition=3rd ed.}}</ref> During translation, genetic material called [[mRNA]] is read by [[ribosomes]] to generate a protein [[polypeptide]] chain.<ref name=Weaver /> This process requires [[TRNA|transfer RNA]] (tRNA) which serves as an adaptor by binding [[amino acids]] on one end and interacting with mRNA at the other end; the latter pairing between the tRNA and mRNA ensures that the correct amino acid is added to the chain.<ref name=Weaver /> Protein synthesis occurs in three phases: initiation, elongation, and termination.<ref name="Watson's Molecular Biology of the Gene" /> [[Prokaryotic translation]] differs from [[eukaryotic translation]]; however, this section will mostly focus on the commonalities between the two organisms.
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| ===Additional background===
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| Before translation can begin, the process of binding a specific amino acid to its corresponding tRNA must occur. This reaction, called tRNA charging, is catalyzed by [[aminoacyl tRNA synthetase]].<ref name=Copper>{{cite book|last=Cooper|first=Geoffrey M.|title=The cell : a molecular approach|year=2000|publisher=ASM Press|location=Washington (DC)|isbn=978-0878931064|edition=2nd ed.}}</ref> A specific tRNA synthetase is responsible for recognizing and charging a particular amino acid.<ref name=Copper /> Furthermore, this enzyme has special discriminator regions to ensure the correct binding between tRNA and its cognate amino acid.<ref name=Copper /> The first step for joining an amino acid to its corresponding tRNA is the formation of aminoacyl-AMP:<ref name=Copper />
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| <math> Amino~acid + ATP \rightleftharpoons{} aminoacyl~AMP + PP_i</math>
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| This is followed by the transfer of the aminoacyl group from aminoacyl-AMP to a tRNA molecule. The resulting molecule is [[aminoacyl-tRNA]]:<ref name=Copper />
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| <math> Aminoacyl~AMP + tRNA \rightleftharpoons {} aminoacyl~tRNA + AMP</math>
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| The combination of these two steps, both of which are catalyzed by aminoacyl tRNA synthetase, produces a charged tRNA that is ready to add amino acids to the growing polypeptide chain.
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| In addition to binding an amino acid, tRNA has a three nucleotide unit called an [[Anticodon#Anticodon|anticodon]] that [[Basepairing|base pairs]] with specific nucleotide triplets on the mRNA called [[codons]]; codons encode a specific amino acid.<ref name=Jackson>{{cite journal|last=Jackson et al.|first=R.J.|title=The mechanism of eukaryotic translation initiation and principles of its regulation|journal=Molecular Cell Biology|date=February 2010|volume=10|pages=113–127|accessdate=25 November 2013}}</ref> This interaction is possible thanks to the ribosome, which serves as the site for protein synthesis. The ribosome possesses three tRNA binding sites: the aminoacyl site (A site), the peptidyl site (P site), and the exit site (E site).<ref name=Green>{{cite journal|last=Green et al|first=Rachel|coauthors=Harry F. Noller|title=Ribosomes and Translation|journal=Annu. Rev. Biochem|year=1997|volume=66|pages=679–716|accessdate=25 November 2013}}</ref>
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| There are numerous codons within an mRNA transcript, and it is very common for an amino acid to be specified by more than one codon; this phenomenon is called [[Codon degeneracy|degeneracy]].<ref name=Weissbach>{{cite book|last=Pestka (editors)|first=Herbert Weissbach, Sidney|title=Molecular Mechanisms of protein biosynthesis.|year=1977|publisher=Academic Press|location=New York|isbn=0127442502}}</ref> In all, there are 64 codons, 61 of each code for one of the 20 amino acids, while the remaining codons specify chain termination.<ref name=Weissbach />
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| ===Translation in steps===
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| As previously mentioned, translation occurs in three phases: initiation, elongation, and termination.
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| [[File:TRNA ribosomes diagram en.svg|311x440px|framed|left|Translation]]
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| ====Step 1: Initiation====
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| The completion of the initiation phase is dependent on the following three events:<ref name="Watson's Molecular Biology of the Gene" />
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| 1. The recruitment of the ribosome to mRNA
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| 2. The binding of a charged initiator tRNA into the P site of the ribosome
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| 3. The proper alignment of the ribosome with mRNA’s start codon
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| ====Step 2: Elongation====
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| Following initiation, the polypeptide chain is extended via anticodon:codon interactions, with the ribosome adding amino acids to the polypeptide chain one at a time. The following steps must occur to ensure the correct addition of amino acids:<ref name=Frank>{{cite journal|last=Frank|first=J|coauthors=Haixiao Gao et al|title=The process of mRNA–tRNA translocation|journal=PNAS|date=September 2007|volume=104|issue=50|pages=19671–19678|url=http://www.pnas.org/content/104/50/19671.long#sec-8|accessdate=26 November 2013}}</ref>
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| 1. The binding of the correct tRNA into the A site of the ribosome
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| 2. The formation of a [[peptide bond]] between the tRNA in the A site and the polypeptide chain attached to the tRNA in the P site
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| 3. [[Protein translocation#Protein translocation|Translocation]] or advancement of the tRNA-mRNA complex by three nucleotides
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| Translocation “kicks off” the tRNA at the E site and shifts the tRNA from the A site into the P site, leaving the A site free for an incoming tRNA to add another amino acid.
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| ====Step 3: Termination====
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| The last stage of translation occurs when a [[stop codon]] enters the A site.<ref name=isbn0-8153-3218-1 /> Then, the following steps occur:
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| 1. The recognition of codons by [[release factor]]s, which causes the [[hydrolysis]] of the polypeptide chain from the tRNA located in the P site<ref name=isbn0-8153-3218-1 />
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|
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| 2. The release of the polypeptide chain <ref name=Weissbach/>
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| 3. The dissociation and "recycling" of the ribosome for future translation processes <ref name=Weissbach/>
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| A summary table of the key players in translation is found below:
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| {| class="wikitable"
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| |+
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| ! '''Key players in Translation''' || '''Translation Stage'''|| '''Purpose'''
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| |-
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| | align=''center'' | tRNA synthetase''' || before initiation || Responsible for tRNA charging
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| |-
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| | align=''center'' | mRNA''' || initiation, elongation, termination ||Template for protein synthesis; contains regions named codons which encode amino acids
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| |-
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| | align=''center'' | tRNA''' || initiation, elongation, termination ||Binds ribosomes sites A, P, E; anticodon base pairs with mRNA codon to ensure that the correct amino acid is incorporated into the growing polypeptide chain
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| |-
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| | align=''center'' | ribosome''' || initiation, elongation, termination||Directs protein synthesis and catalyzes the formation of the peptide bond
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| |-
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| |}
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| {{-}}
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| ==Diseases associated with macromolecule deficiency==
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| [[File:Xanthelasma palpebrarum.jpg|180x180px|thumbnail|right|Familial hypercholesterolemia causes cholesterol deposits]]
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| Errors in biosynthetic pathways can have deleterious consequences including the malformation of macromolecules or the underproduction of functional molecules. Below are examples that illustrate the disruptions that occur due to these inefficiencies.
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| *[[Familial hypercholesterolemia]]: this disorder is characterized by the absence of functional [[Receptor (biochemistry)|receptors]] for [[LDL]].<ref name="Bandeali- Familial hypercholesterolemia">{{cite journal|last=Bandeali|first=Salman J.|coauthors=Daye, Jad; Virani, Salim S.|title=Novel Therapies for Treating Familial Hypercholesterolemia|journal=Current Atherosclerosis Reports|date=30 November 2013|volume=16|issue=1|doi=10.1007/s11883-013-0382-0|accessdate=9 December 2013}}</ref> Deficiencies in the formation of LDL receptors may cause faulty receptors which disrupt the [[Endocytosis|endocytic]] pathway, inhibiting the entry of LDL into the liver and other cells.<ref name="Bandeali- Familial hypercholesterolemia" /> This causes a buildup of LDL in the blood plasma, which results in [[atherosclerotic plaques]] that narrow arteries and increase the risk of heart attacks.<ref name="Bandeali- Familial hypercholesterolemia" />
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| *[[Lesch-Nyhan syndrome]]: this genetic disease is characterized by [[Self mutilation|self- mutilation]], mental deficiency, and [[gout]].<ref name="Kang- Lesch-Nyhan syndrome">{{cite journal|last=Kang|first=Tae Hyuk|coauthors=Park, Yongjin; Bader, Joel S.; Friedmann, Theodore; Cooney, Austin John|title=The Housekeeping Gene Hypoxanthine Guanine Phosphoribosyltransferase (HPRT) Regulates Multiple Developmental and Metabolic Pathways of Murine Embryonic Stem Cell Neuronal Differentiation|journal=PLoS ONE|date=9 October 2013|volume=8|issue=10|pages=e74967|doi=10.1371/journal.pone.0074967}}</ref> It is caused by the absence of [[hypoxanthine-guanine phosphoribosyltransferase]], which is a necessary enzyme for purine nucleotide formation.<ref name="Kang- Lesch-Nyhan syndrome" /> The lack of enzyme reduces the level of necessary nucleotides and causes the accumulation of biosynthesis [[Reaction intermediate|intermediates]], which results in the aforementioned unusual behavior.<ref name="Kang- Lesch-Nyhan syndrome" />
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| *[[Severe combined immunodeficiency|Severe combined immunodeficiency (SCID)]]: SCID is characterized by a loss of [[T cells]].<ref name="Janeway's Immunobiology">{{cite book|last=Walport|first=Ken Murphy, Paul Travers, Mark|title=Janeway's Immunobiology|year=2011|publisher=Taylor & Francis|location=Oxford|isbn=978-0815342434|edition=8. ed.}}</ref> Shortage of these immune system components increases the susceptibility to infectious agents because the affected individuals cannot develop [[Immunological memory|immunological]] memory.<ref name="Janeway's Immunobiology" /> This immunological disorder results from a deficiency in [[Adenosine deaminase|adenosine deanimase]] activity, which causes a buildup of [[dATP]]. These dATP molecules then inhibit ribonucleotide reductase, which prevents of DNA synthesis.<ref name="Janeway's Immunobiology" />
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| *[[Huntingtons disease|Huntington’s disease]]: this [[neurological]] disease is caused from errors that occur during DNA synthesis.<ref name="Hughes_Huntington's">{{cite book|last=Hughes|first=edited by Donald C. Lo, Robert E.|title=Neurobiology of Huntington's disease : applications to drug discovery|year=2010|publisher=CRC Press/Taylor & Francis Group|location=Boca Raton|isbn=978-0849390005|edition=2nd ed.}}</ref> These errors or mutations lead to the expression of a mutant [[huntingtin]] protein, which contains repetitive [[glutamine]] residues that are encoded by expanding [[Trinucleotide repeat#CAG Repeats|CAG trinucleotide repeats]] in the gene.<ref name="Hughes_Huntington's" /> Huntington’s disease is characterized by neuronal loss and [[gliosis]]. Symptoms of the disease include: movement disorder, [[cognitive]] decline, and behavioral disorder.<ref name="Biglan- Huntington's">{{cite journal|last=Biglan|first=Kevin M.|coauthors=Ross, Christopher A.; Langbehn, Douglas R.; Aylward, Elizabeth H.; Stout, Julie C.; Queller, Sarah; Carlozzi, Noelle E.; Duff, Kevin; Beglinger, Leigh J.; Paulsen, Jane S.|title=Motor abnormalities in premanifest persons with Huntington's disease: The PREDICT-HD study|journal=Movement Disorders|date=26 June 2009|volume=24|issue=12|pages=1763–1772|doi=10.1002/mds.22601|accessdate=9 December 2013}}</ref>
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| {{-}}
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| ==See also==
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| * [[Lipids]]
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| * [[Phosopholipid bilayer|Phospholipid bilayer]]
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| * [[Nucleotides]]
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| * [[DNA]]
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| * [[DNA replication]]
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| * [[Amino acids]]
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| * [[Proteinogenic amino acid]]
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| * [[Codon table#RNA codon table|Codon table]]
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| * [[Proteins]]
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| * [[Translation (biology)|Translation]]
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| ==References==
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| {{reflist|2}}
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| [[Category:Metabolism]]
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| [[Category:Biosynthesis| ]]
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