View source for Acetyl-CoA carboxylase

{{enzyme
| Name = Acetyl-CoA carboxylase
| EC_number = 6.4.1.2
| CAS_number = 9023-93-2
| IUBMB_EC_number = 6/4/1/2
| GO_code = 0003989
| image = 
| width = 
| caption = 
}}
{{Infobox protein
|Name=[[ACACA|Acetyl-CoA carboxylase alpha]]
|Symbol=[[ACACA]] ||AltSymbols=ACAC, ACC1, ACCA
|HGNCid=84 ||Chromosome=17 ||Arm=q ||Band=21
|LocusSupplementaryData= ||ECnumber=6.4.1.2
|OMIM=601557 ||EntrezGene=31 ||RefSeq=NM_198839
|UniProt=Q13085
}}
{{Infobox protein
|Name=[[ACACB|Acetyl-CoA carboxylase beta]]
|Symbol=[[ACACB]] ||AltSymbols=ACC2, ACCB ||HGNCid=85
|Chromosome=12 ||Arm=q ||Band=24.1
|LocusSupplementaryData= ||ECnumber=6.4.1.2
|OMIM=200350 ||EntrezGene=32 ||RefSeq=NM_001093
|UniProt=O00763
}}
<!-- TEXT STARTS HERE -->'''Acetyl-CoA carboxylase''' ('''ACC''') is a [[biotin]]-dependent [[enzyme]] that catalyzes the irreversible carboxylation of [[acetyl-CoA]] to produce [[malonyl-CoA]] through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is a multi-subunit enzyme in most [[prokaryotes]] and in the [[chloroplast]]s of most plants and algae, whereas it is a large, multi-domain enzyme in the [[endoplasmic reticulum]] of most [[eukaryotes]]. The most important function of ACC is to provide the malonyl-CoA substrate for the [[fatty acid biosynthesis|biosynthesis of fatty acids]].<ref name="pmid15968460">{{cite journal | author = Tong L | title = Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery | journal = Cell. Mol. Life Sci. | volume = 62 | issue = 16 | pages = 1784–803 |date=August 2005 | pmid = 15968460 | doi = 10.1007/s00018-005-5121-4 | url =  }}</ref> The activity of ACC can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. The human genome contains the genes for two different ACCs<ref name="pmid9449982">{{cite journal |vauthors=Brownsey RW, Zhande R, Boone AN | title = Isoforms of acetyl-CoA carboxylase: structures, regulatory properties and metabolic functions | journal = Biochem. Soc. Trans. | volume = 25| issue = 4 | pages = 1232–8 |date=November 1997 | pmid = 9449982 | doi = | url = | issn = }}</ref>—[[ACACA]]<ref name="pmid7732023">{{cite journal |vauthors=Abu-Elheiga L, Jayakumar A, Baldini A, Chirala SS, Wakil SJ | title = Human acetyl-CoA carboxylase: characterization, molecular cloning, and evidence for two isoforms | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 92 | issue = 9 | pages = 4011–5 |date=April 1995 | pmid = 7732023 | pmc = 42092 | doi = 10.1073/pnas.92.9.4011| url = }}</ref> and [[ACACB]].<ref name="pmid8670171">{{cite journal |vauthors=Widmer J, Fassihi KS, Schlichter SC, Wheeler KS, Crute BE, King N, Nutile-McMenemy N, Noll WW, Daniel S, Ha J, Kim KH, Witters LA | title = Identification of a second human acetyl-CoA carboxylase gene | journal = Biochem. J. | volume = ( Pt 3) | issue = | pages = 915–22 |date=June 1996 | series = 316  | pmid = 8670171 | pmc = 1217437 | doi = | url = http://www.biochemj.org/bj/316/0915/bj3160915.htm | issn = }}</ref>

== Structure ==
[[Prokaryotes]] and [[plants]] have multi-subunit ACCs composed of several polypeptides encoded by distinct genes. Biotin carboxylase (BC) activity, biotin carboxyl carrier protein (BCCP), and carboxyl transferase (CT) activity are each contained on a different subunit. The stoichiometry of these subunits in the ACC [[holoenzyme]] differs amongst organisms.<ref name="pmid15968460" /> [[Humans]] and most [[eukaryotes]] have evolved an ACC with CT and BC catalytic domains and biotin carboxyl carrier domains on a single polypeptide. ACC functional regions, starting from the [[N-terminus]] to [[C-terminus]] are the biotin carboxylase (BC), biotin binding (BB), carboxyltransferase (CT), and ATP-binding (AB). AB lies within BC. [[Biotin]] is covalently attached through an amide bond to the long [[side chain]] of a lysine reside in BB. As BB is between BC and CT regions, biotin can easily translocate to both of the active sites where it is required.

In mammals where two isoforms of ACC are expressed, the main structural difference between these isoforms is the extended ACC2 N-terminus containing a mitochondria targeting sequence.<ref name="pmid15968460"/>

{{Gallery
|title=Crystallographic structures of ''E. coli'' acetyl-CoA carboxylase
|width=270
|lines=3
|Image:Biotin_carboxylase_rainbow.png|Biotin carboxylase subunit of ''E. coli'' acetyl-CoA carboxylase
|Image:BCCP.png|Biotin carboxyl carrier protein subunit of ''E. coli'' acetyl-CoA carboxylase
|Image:Carboxytransferase_2F9Y_E-Coli.png|Carboxyl transferase subunit of ''E. coli'' acetyl-CoA carboxylase
}}

== Mechanism ==
The overall reaction of ACAC(A,B) proceeds by a two-step mechanism.<ref name="pmid18247344">{{cite journal |vauthors=Lee CK, Cheong HK, Ryu KS, Lee JI, Lee W, Jeon YH, Cheong C | title = Biotinoyl domain of human acetyl-CoA carboxylase: Structural insights into the carboxyl transfer mechanism | journal = Proteins | volume = 72 | issue = 2 | pages = 613–24 |date=August 2008 | pmid = 18247344 | doi = 10.1002/prot.21952 | url =  }}</ref> The first reaction is carried out by BC and involves the ATP-dependent carboxylation of [[biotin]] with [[bicarbonate]] serving as the source of CO<sub>2</sub>. The carboxyl group is transferred from [[biotin]] to [[acetyl CoA]] to form [[malonyl CoA]] in the second reaction, which is catalyzed by CT.

[[File:ACAC mechanism.png|frame|center|627px|<div style="border-width: 0px; border-bottom: 1px solid black; text-align: left;">'''The reaction mechanism of ACAC(A,B)'''.</div>The color scheme is as follows: <span style="font-weight: bold;"><span style="color: blue;">enzyme</span>, <span style="color: rgb(219,155,36);">coenzymes</span>, <span style="color: rgb(151,149,45);">substrate names</span>, <span style="color: rgb(227,13,196);">metal ions</span>, <span style="color: rgb(128,0,0);">phosphate</span>, and <span style="color: red;">carbonate</span> </span>]]

In the [[active site]], the reaction proceeds with extensive interaction of the residues Glu296 and positively charged Arg338 and Arg292 with the substrates.<ref name="pmid19213731">{{cite journal |vauthors=Chou CY, Yu LP, Tong L |title=Crystal structure of biotin carboxylase in complex with substrates and implications for its catalytic mechanism |journal=J. Biol. Chem. |volume=284 |issue=17 |pages=11690–7 |date=April 2009 |pmid=19213731 |pmc=2670172 |doi=10.1074/jbc.M805783200 |url=}}</ref>  Two Mg2+ are coordinated by the phosphate groups on the [[Adenosine triphosphate|ATP]], and are required for ATP binding to the enzyme.  Bicarbonate is deprotonated by Glu296, although in solution, this proton transfer is unlikely as the [[pKa]] of [[bicarbonate]] is 10.3.  The [[enzyme]] apparently manipulates [[Acid dissociation constant|pKas]] to facilitate the deprotonation of bicarbonate.  The pKa of [[bicarbonate]] is decreased by its interaction with positively charged side chains of Arg338 and Arg292.  Furthermore, Glu296 interacts with the side chain of Glu211, an interaction that has been shown to cause an increase in the apparent pKa. Following deprotonation of bicarbonate, the oxygen of the bicarbonate acts as a [[nucleophile]] and attacks the gamma phosphate on ATP.  The carboxyphosphate intermediate quickly decomposes to CO<sub>2</sub> and PO<sub>4</sub><sup>3−</sup>. The PO<sub>4</sub><sup>3−</sup> deprotonates biotin, creating an enolate, stabilized by Arg338, that subsequently attacks [[CO<sub>2</sub>]]  resulting in the production of carboxybiotin.<ref name="pmid19213731"/> The carboxybiotin translocates to the carboxytransferase (CT) active site, where the carboxyl group is transferred to acetyl-CoA.  In contrast to the BC domain, little is known about the reaction mechanism of CT.  A proposed mechanism is the release of [[carbon dioxide]] from biotin, which subsequently abstracts a proton from the methyl group from acetyl CoA carboxylase.  The resulting [[enolate]] attacks CO<sub>2</sub> to form malonyl CoA. In a competing mechanism, [[proton]] abstraction is concerted with the attack of acetyl CoA.

==Function==
The function of ACC is to regulate the metabolism of fatty acids. When the enzyme is active, the product, malonyl-CoA, is produced which is a building block for new fatty acids and can inhibit the transfer of the fatty acyl group from acyl CoA to [[carnitine]] with [[carnitine acyltransferase]], which inhibits the [[beta-oxidation]] of fatty acids in the [[mitochondria]].

In [[mammals]], two main [[isoforms]] of ACC are expressed, ACC1 and ACC2, which differ in both tissue distribution and function. ACC1 is found in the [[cytoplasm]] of all cells but is enriched in lipogenic tissue, such as [[adipose]] tissue and lactating [[mammary glands]], where fatty acid synthesis is important.<ref name="pmid8753813">{{cite journal |vauthors=Kim TS, Leahy P, Freake HC |title=Promoter usage determines tissue specific responsiveness of the rat acetyl-CoA carboxylase gene |journal=Biochem. Biophys. Res. Commun. |volume=225 |issue=2 |pages=647–53 |date=August 1996 |pmid=8753813 |doi=10.1006/bbrc.1996.1224 |url=}}</ref> In oxidative tissues, such as the [[skeletal muscle]] and the [[heart]], the ratio of ACC2 expressed is higher. ACC1 and ACC2 are both highly expressed in the [[liver]] where both fatty acid oxidation and synthesis are important.<ref name="pmid15749055">{{cite journal |vauthors=Barber MC, Price NT, Travers MT |title=Structure and regulation of acetyl-CoA carboxylase genes of metazoa |journal=Biochim. Biophys. Acta |volume=1733 |issue=1 |pages=1–28 |date=March 2005 |pmid=15749055 |doi=10.1016/j.bbalip.2004.12.001 |url=}}</ref>  The differences in tissue distribution indicate that ACC1 maintains regulation of fatty acid synthesis whereas ACC2 mainly regulates fatty acid oxidation.

== Regulation ==
[[File:Control of Acetyl CoA Carboxylase corrected.png|500px|right|thumb|'''Control of Acetyl CoA Carboxylase.''' 
The AMP regulated kinase triggers the phosphorylation of the enzyme (thus inactivating it) and the phosphatase enzyme removes the phosphate group.]]

The regulation of mammalian ACC is complex, in order to control two distinct pools of [[malonyl CoA]] that direct either the inhibition of beta oxidation or the activation of lipid biosynthesis.<ref name=pmid1128337 />

Mammalian ACC1 and ACC2 are regulated transcriptionally by multiple [[promoter (biology)|promoters]] which mediate ACC abundance in response to the cells nutritional status.  Activation of gene expression through different promoters results in alternative splicing; however, the physiological significance of specific ACC [[isozymes]] remains unclear.<ref name="pmid15749055"/> The sensitivity to nutritional status results from the control of these promoters by [[transcription factors]] such as [[SREBP1c]], controlled by insulin at the transcriptional level, and [[ChREBP]], which increases in expression with high [[carbohydrates]] diets.<ref name="pmid12213084">{{cite journal |author1=Field F. J. |author2=Born E. |author3=Murthy S. |author4=Mathur S. N. | title = Polyunsaturated fatty acids decrease the expression of sterol regulatory element binding protein-1 in CaCo-2 cells: effect on fatty acid synthesis and triacylglycerol transport. | journal = Biochem. J. | volume = 368 | issue = Pt 3 | pages = 855–64 |date=December 2002 | pmid = 12213084 | doi = 10.1042/BJ20020731 | url = | pmc = 1223029  }}</ref><ref name="pmid15496471">{{cite journal |vauthors=Ishii S, Iizuka K, Miller BC, Uyeda K | title = Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription | journal = Proc Natl Acad Sci USA | volume = 101 | issue = 44 | pages = 15597–602 |date=October 2004 | pmid = 15496471 | doi = 10.1073/pnas.0405238101 | url = | pmc = 524841  }}</ref>

Through a feedforward loop, [[citrate]] allosterically activates ACC.<ref name="pmid14470343">{{cite journal |vauthors=Martin DB, Vagelos PR | title = The Mechanism of Tricarboxylic Acid Cycle Regulation of Fatty Acid Synthesis | journal = J Biol Chem | volume = 237 | issue =  | pages = 1787–92 |date=June 1962 | pmid = 14470343 | doi =  | url =  }}</ref> Citrate may increase ACC [[polymerization]] to increase enzymatic activity; however, it is unclear if polymerization is citrate's main mechanism of increasing ACC activity or if polymerization is an artifact of in vitro experiments. Other allosteric activators include [[glutamate]] and other [[dicarboxylic acids]].<ref name="pmid10753875">{{cite journal |vauthors=Boone AN, Chan A, Kulpa JE, Brownsey RW | title = Bimodal Activation of Acetyl-CoA Carboxylase by Glutamate | journal = J Biol Chem | volume = 275 | issue = 15 | pages = 10819–25 |date=April 2000 | pmid = 10753875 | doi = 10.1074/jbc.275.15.10819  | url =  }}</ref> Long and short chain fatty acyl CoAs are negative feedback inhibitors of ACC.<ref name="pmid9173866">{{cite journal |vauthors=Faergeman NJ, Knudsen J | title = Role of long chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling | journal = Biochem. J. | volume = 323 | issue = Pt 1 | pages = 1–12 |date=April 1997 | pmid = 9173866 | doi =   | url = | pmc = 1218279  }}</ref>

Phosphorylation can result when the hormones [[glucagon]] or [[epinephrine]] bind to cell surface [[Receptor (biochemistry)|receptors]], but the main cause of phosphorylation is due to a rise in AMP levels when the energy status of the cell is low, leading to the activation of the AMP-activated protein kinase (AMPK). AMPK is the main [[kinase]] regulator of ACC, able to phosphorylate a number of serine residues on both isoforms of ACC.<ref name="pmid12015362">{{cite journal |vauthors=Park SH, Gammon SR, Knippers JD, Paulsen SR, Rubink DS, Winder WW |title=Phosphorylation-activity relationships of AMPK and acetyl-CoA carboxylase in muscle |journal=J. Appl. Physiol. |volume=92 |issue=6 |pages=2475–82 |date=June 2002 |pmid=12015362 |doi=10.1152/japplphysiol.00071.2002 |url=}}</ref> On ACC1, AMPK phosphorylates Ser79, Ser1200, and Ser1215. [[Protein kinase A]] also has the ability to phosphorylate ACC, with a much greater ability to phosphorylate ACC2 than ACC1.  However, the physiological significance of protein kinase A in the regulation of ACC is currently unknown. Researchers hypothesize there are other ACC kinases important to its regulation as there are many other possible phosphorylation sites on ACC.<ref name="pmid16545081 ">{{cite journal |vauthors=Brownsey RW, Boone AN, Elliott JE, Kulpa JE, Lee WM |title=Regulation of acetyl-CoA carboxylase |journal=Biochem. Soc. Trans. |volume=34 |issue=Pt 2 |pages=223–7 |date=April 2006 |pmid=16545081 |doi=10.1042/BST20060223 |url=}}</ref>

When [[insulin]] binds to its receptors on the cellular [[Cell membrane|membrane]], it activates a phosphatase enzyme called protein phosphatase 2A (PP2A) to dephosphorylate the enzyme; thereby removing the inhibitory effect. Furthermore, insulin induces a phosphodiesterase that lowers the level of cAMP in the cell, thus inhibiting PKA, and also inhibits AMPK directly.

This protein may use the [[morpheein]] model of [[allosteric regulation]].<ref name=pmid22182754>{{cite journal |author1=T. Selwood |author2=E. K. Jaffe. | title = Dynamic dissociating homo-oligomers and the control of protein function. | journal =  Arch. Biochem. Biophys. | volume =  519| issue =  2| pages =  131–43| year = 2011 | pmid = 22182754 | doi=10.1016/j.abb.2011.11.020 | pmc=3298769}}</ref>

== Clinical implications ==
At the juncture of lipid synthesis and oxidation pathways, ACC presents many clinical possibilities for the production of novel [[antibiotics]] and the development of new therapies for [[diabetes]], [[obesity]], and other manifestations of [[metabolic syndrome]].<ref name="pmid18221116">{{cite journal |vauthors=Corbett JW, Harwood JH | title = Inhibitors of mammalian acetyl-CoA carboxylase | journal = Recent Patents Cardiovasc Drug Discov | volume = 2 | issue = 3 | pages = 162–80 |date=November 2007 | pmid = 18221116 | doi = 10.2174/157489007782418928| url =  }}</ref> Researchers aim to take advantage of structural differences between bacterial and human ACCs to create [[antibiotics]] specific to the bacterial ACC, in efforts to minimize side effects to patients. Promising results for the usefulness of an ACC inhibitor include the finding that ACC2 -/- mice (mice with no expression of ACC2) have continuous fatty acid oxidation, reduced body fat mass, and reduced body weight despite an increase in food consumption. ACC2 -/- mice are also protected from diabetes.<ref name="pmid1128337">{{cite journal |author1=L Abu-Elheiga |author2=M M Matzuk |author3=K A Abo-Hashema |author4=S J Wakil | title = Continuous Fatty Acid Oxidation and Reduced Fat Storage in Mice Lacking Acetyl-CoA Carboxylase 2 | journal = Science | volume = 291 | issue = 5513 | pages = 2613–6 |date=March 2001 | pmid = 11283375 | doi = 10.1126/science.1056843| url =  }}</ref> It should be noted that a lack of ACC1 in mutant mice is lethal already at the embryonic stage.  However, it is unknown whether drugs targeting ACCs in humans must be specific for ACC2.<ref name="pmid16103361">{{cite journal |author1=Lutfi Abu-Elheiga |author2=Martin M Matzuk |author3=Parichher Kordari |author4=WonKeun Oh |author5=Tattym Shaikenov |author6=Ziwei Gu |author7=Salih J Wakil | title = Mutant Mice Lacking Acetyl CoA Carboxylase are Embryonically Lethal | journal = Proc. Natl. Acad. Sci. USA | volume = 102 | issue = 34 | pages = 1211–6 |date=August 2005 | pmid = 16103361 | doi = 10.1073/pnas.0505714102| url = | pmc =  1189351  }}</ref>  An allosteric inhibitor of ACC has been granted fast-track status for the treatment of NASH (non-alcoholic steatohepatitis).<ref>http://www.nimbustx.com/our-pipeline</ref>

==See also==
* [[Malonyl-CoA decarboxylase]]

== References ==

{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite book |last1= Voet |first1= Donald |last2= Voet |first2= Judith G. |title= Biochemistry |edition=3rd |year= 2004 |publisher= Wiley |isbn= 0-471-19350-X}}
* {{cite book |editor1-last= Buchanan |editor1-first= Bob B. |editor2-last= Gruissem |editor2-first= Wilhelm |editor3-last= Jones | editor3-first= Russell L. |title= Biochemistry and molecular biology of plants |year= 2000 |publisher= American Society of Plant Physiologists |isbn= 0-943088-37-2 |author = edited by}}
* {{cite journal |vauthors=Levert K, Waldrop G, Stephens J |title=A biotin analog inhibits acetyl-CoA carboxylase activity and adipogenesis |journal=J. Biol. Chem. |volume=277 |issue=19 |pages=16347–50 |year=2002 |pmid=11907024 |url= |doi=10.1074/jbc.C200113200}}
{{refend}}

{{Lipid metabolism enzymes}}
{{Carbon-carbon ligases}}
{{Enzymes}}
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{{DEFAULTSORT:Acetyl-Coa Carboxylase}}
[[Category:EC 6.4.1]]