imported>Subpagination Bot |
imported>David E. Volk |
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| [[Image:Acetyl-coenzyme-A-3D-vdW.png|thumb|400px|Acetyl-CoA]] --> | | [[Image:Acetyl-coenzyme-A-3D-vdW.png|thumb|400px|Acetyl-CoA]] --> |
| '''Coenzyme A''' ('''CoA''', '''CoA-SH''', or '''HS-CoA''') is a [[coenzyme]], notable for its role in the [[Fatty acid metabolism#Synthesis|synthesis]] and [[Fatty acid metabolism#.CE.B2-Oxidation|oxidization]] of [[fatty acid]]s, and the oxidation of [[pyruvic acid|pyruvate]] in the [[citric acid cycle]]. It is synthesized from [[beta-mercaptoethylamine|β-mercaptoethylamine]], [[pantothenic acid|panthothenate]] and [[adenosine triphosphate]]. | | '''Coenzyme A''' ('''CoA''', '''CoA-SH''', or '''HS-CoA''') is a [[coenzyme]], notable for its role in the [[Fatty acid metabolism#Synthesis|synthesis]] and [[Fatty acid metabolism#.CE.B2-Oxidation|oxidization]] of [[fatty acid]]s, and the oxidation of [[pyruvic acid|pyruvate]] in the [[citric acid cycle]]. It is synthesized from [[beta-mercaptoethylamine|β-mercaptoethylamine]], [[pantothenic acid|panthothenate]] and [[adenosine triphosphate]]. |
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| ==Function==
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| The main function of coenzyme A is to carry [[acyl]] groups (such as the [[acetyl]] group) or [[thioesters]]. A molecule of coenzyme A carrying an [[acetyl]] group is also referred to as '''acetyl-CoA'''. It is sometimes referred to as 'CoA-SH' or 'HS-CoA' because its reactivity is due to a [[thiol]] group, -SH.
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| Acetyl-CoA is an important molecule itself. It is the precursor to 3-hydroxy-3-methylglutaryl CoA (HMG CoA), which is a key intermediate in [[cholesterol]] and [[Ketone bodies|ketogenesis]]. It is also an acetyl donor to [[choline]] to produce [[acetylcholine]], in a reaction catalysed by [[choline acetyltransferase]]. Its main task is conveying the [[carbon]] [[atom]]s within the acetyl group to the [[citric acid cycle]] to be [[oxidation|oxidized]] for energy production.
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| ==Pyruvate Dehydrogenase Reaction==
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| The conversion of [[pyruvate]] into acetyl-CoA is catalyzed by an enzyme-complex called [[pyruvate dehydrogenase]]. The enzyme consists of 60 [[subunits]]: 24 pyruvate dehydrogenase, 24 [[dihydrolipoyl transacetylase]], and 12 [[dihydrolipoyl dehydrogenase]] (commonly denoted E1, E2, and E3). The pyruvate dehydrogenase subunits contain the [[coenzyme]] [[thiamin|TPP (thiamin pyrophosphate)]], dihydrolipoyl transacetylase subunits carry [[Lipoic_acid|lipoate]] and coenzyme A, and the dihydrolipoyl dehydrogenase subunits contain the electron-transferring coenzymes [[FAD]] and [[Nicotinamide adenine dinucleotide|NAD]]<sup>+</sup>. <br>The reaction of this complex follows three steps.
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| Initially, pyruvate is bound by pyruvate dehydrogenase subunits and attacked at C2 by the [[zwitterionic form]] (negative charge about C2 of the thiazolium ring) of [[Thiamine|thiamin pyrophosphate]], also bound by the enzyme. This tetrahedral intermediate undergoes decarboxylation resulting in an acyl anion equivalent (see [[cyanohydrin]] or aldehyde-dithiane [[umpoloung]] chemistry, as well as [[Benzoin Condensation|benzoin condensation]]). This anion attacks the S1 of the oxidized lipoate species in an Sn2-like mechanism that displaces the S2 thiol as a sulfide or sulfhydryl moiety.
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| Subsequent breakdown of the thiazole-hemithioacetal species ejects the TPP cofactor and generates an S1 thioester about the lipoate moiety. At this point, the lipoate-thioester functionality is translocated into the lipoate transacetylase active site, where it undergoes a transacylation with coenzyme A, generating dihydrolipoate and acetyl CoA which subsequently enters the citric acid cycle. The dihydrolipoate moiety then migrates to the dihydrolipoyl dehydrogenase active site where it undergoes FAD-mediated oxidation (identical in chemistry to [[disulfide isomerase]]) which returns lipoate to its resting state and generates FADH2, which is further oxidized by the bound nicotinamide cofactor producing NADH2 and regenerated flavin.
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| ==Metabolism==
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| Coenzyme A is central to the balance between [[carbohydrate]] [[metabolism]] and [[fat]] metabolism. Normally, acetyl-CoA from fatty acid metabolism feeds into the [[citric acid cycle]], contributing to the cell's energy supply. In the liver, when levels of circulating fatty acids are high, the production of acetyl-CoA from fat breakdown exceeds the cellular energy requirements. To make use of the energy available from the excess acetyl-CoA, [[ketone bodies]] are produced which can then circulate in the blood.
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| In some circumstances this can lead to an excess of ketone bodies in the blood, a condition known as [[ketoacidosis]]. This can occur in [[diabetes mellitus|diabetes]], starvation or in people following [[low-carbohydrate diet]]s, all of which can cause fats to be metabolised as a major source of energy.
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| == See also ==
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| * [[Citric acid cycle]]
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| * [[HMG-CoA reductase pathway]]
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| * [[Fatty acid metabolism]]
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| == References ==
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| * Karl Miller (1998). [http://www.gwu.edu/~mpb/betaox.htm Beta Oxidation of Fatty Acids]. Retrieved May 18, 2005.
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| * Charles Ophard (2003). [http://www.elmhurst.edu/~chm/vchembook/623acetylCoAfate.html Acetyl-CoA Crossroads]. Retrieved May 18, 2005.
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| *''Lehninger Principles of Biochemistry'', 4th edition, David L. Nelson, Michael M. Cox
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