Malonyl-CoA

Malonyl-CoA is a coenzyme A derivative of malonic acid.

Malonyl-CoA

Names
Preferred IUPAC name (9R)-1-[(2R,3S,4R,5R)-5-(6-Amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)oxolan-2-yl]-3,5,9-trihydroxy-3,5,10,14,19-pentaoxo-8,8-dimethyl-2,4,6-trioxa-18-thia-11,15-diaza-3λ5,5λ5-diphosphahenicosan-21-oic acid
Identifiers
CAS Number	524-14-1 (free acid) Y 116928-84-8 (tetralithium salt)
ChemSpider	559121 Y
ECHA InfoCard	100.007.596
MeSH	Malonyl+CoA
PubChem CID	644066
UNII	LNB9YCJ9F9 (free acid) Y
CompTox Dashboard (EPA)	DTXSID40904351
InChI InChI=1S/C24H38N7O19P3S/c1-24(2,19(37)22(38)27-4-3-13(32)26-5-6-54-15(35)7-14(33)34)9-47-53(44,45)50-52(42,43)46-8-12-18(49-51(39,40)41)17(36)23(48-12)31-11-30-16-20(25)28-10-29-21(16)31/h10-12,17-19,23,36-37H,3-9H2,1-2H3,(H,26,32)(H,27,38)(H,33,34)(H,42,43)(H,44,45)(H2,25,28,29)(H2,39,40,41)/t12-,17-,18-,19+,23-/m1/s1 Y Key: LTYOQGRJFJAKNA-DVVLENMVSA-N Y
Properties
Chemical formula	C24H38N7O19P3S
Molar mass	853.582
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Y verify (what is YN ?) Infobox references

Biosynthesis

Malonyl-CoA cannot cross membranes and there is no known malonyl-CoA import mechanism.^[1][2] The biosynthesis therefore takes place locally:

• cytosol: Malonyl-CoA is formed by carboxylating acetyl-CoA using the highly regulated enzyme acetyl-CoA carboxylase 1 (ACC1). One molecule of acetyl-CoA joins with a molecule of bicarbonate,^[3] requiring energy rendered from ATP.
• Mitochondrial outer membrane: Malonyl-CoA is formed by carboxylating acetyl-CoA using the highly regulated enzyme acetyl-CoA carboxylase 2 (ACC2). The reaction is the same as with ACC1.
• mitochondrial matrix: Malonyl-CoA is formed in coordinated fashion by mtACC1, a mitochondrial isoform of ACC1, and acyl-CoA synthetase family member 3 (ACSF3), a mitochondrial malonyl-CoA synthetase.^[4] MtACC1, like cytosolic ACC1 catalyses the carboxylation of acetyl-CoA, while ACSF3 catalyses the thioesterification of malonate to coenzyme A.^[5][4] The latter serves for the clearance of mitochondrial malonate, since malonate is a potent inhibitor of mitochondrial respiration as it competitively inhibits succinate dehydrogenase.^[6] However, the source of malonyl-CoA in the mitochondria is still up for debate.^[2]

Functions

It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis.

Cytosolic malonyl-CoA

Malonyl-CoA provides 2-carbon units to fatty acids and commits them to fatty acid chain synthesis.

Malonyl-CoA is utilised in fatty acid biosynthesis by the enzyme malonyl coenzyme A:acyl carrier protein transacylase (MCAT). MCAT serves to transfer malonate from malonyl-CoA to the terminal thiol of holo-acyl carrier protein (ACP).

Malonyl-CoA is a highly regulated molecule in fatty acid synthesis; as such, it inhibits the rate-limiting step in beta-oxidation of fatty acids.^[6] Malonyl-CoA inhibits fatty acids from associating with carnitine by regulating the enzyme carnitine palmitoyltransferase, thereby preventing them from entering the mitochondria, where fatty acid oxidation and degradation occur.

Polyketide biosynthesis

MCAT is also involved in bacterial polyketide biosynthesis. The enzyme MCAT together with an acyl carrier protein (ACP), and a polyketide synthase (PKS) and chain-length factor heterodimer, constitutes the minimal PKS of type II polyketides.

Clinical relevance

Malonyl-CoA plays a special role in the mitochondrial clearance of toxic malonic acid in the metabolic disorders combined malonic and methylmalonic aciduria (CMAMMA) and malonic aciduria.^[6] In CMAMMA, malonyl-CoA synthetase, ACSF3 is impaired, which generates mitochondrial malonyl-CoA from malonic acid, which can then be converted to acetyl-CoA by malonyl-CoA decarboxylase.^[5][6] In contrast, in malonic aciduria, malonyl-CoA decarboxylase is decreased, which converts malonyl-CoA to acetyl-CoA.^[6]

${\displaystyle \mathrm {Malonic\ acid+CoA+ATP\ {\xrightarrow[{ACSF3}]{Malonyl{-}CoA\ Synthetase}}\ Malonyl{-}CoA\ {\xrightarrow[{MLYCD}]{Malonyl-CoA\ Decarboxylase}}\ Acetyl{-}CoA} }$

See also

• MCAT (gene)