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Structures	Swiss-model
Domains	InterPro

Methylcrotonoyl-coenzyme A carboxylase 1 (alpha)
Methylcrotonoyl-coenzyme A carboxylase 1 (alpha)
Identifiers
Symbol	MCCC1
NCBI gene	56922
HGNC	6936
OMIM	609010
RefSeq	NM_020166
UniProt	Q96RQ3
Other data
EC number	6.4.1.4
Locus	Chr. 3 q27.1
Structures
Search for
Structures	Swiss-model
Domains	InterPro

methylcrotonoyl-CoA carboxylase
Identifiers
Aliases	methylcrotonyl-CoA carboxylase3-methylcrotonoyl-CoA:carbon-dioxide ligase (ADP-forming)beta-methylcrotonyl coenzyme A carboxylaseMCCCmethylcrotonyl coenzyme A carboxylasebeta-methylcrotonyl CoA carboxylasebeta-methylcrotonyl-CoA carboxylase
External IDs	GeneCards: [1]; OMA:- orthologs
Orthologs
	n/a
	n/a
	n/a
	n/a
	n; a
	n/a
	n/a
	n/a
	n/a
	n/a
	Wikidata
View/Edit Human

Methylcrotonoyl-coenzyme A carboxylase 2 (beta)

Identifiers

Symbol

MCCC2

Other data

Chr. 5 q12-q13

Search for
Structures	Swiss-model
Domains	InterPro

Methylcrotonyl CoA carboxylase (EC 6.4.1.4, MCC) (3-methylcrotonyl CoA carboxylase, methylcrotonoyl-CoA carboxylase) is a biotin-requiring enzyme located in the mitochondria. MCC uses bicarbonate as a carboxyl group source to catalyze the carboxylation of a carbon adjacent to a carbonyl group performing the fourth step in processing leucine, an essential amino acid.^[1]

Structure

Gene

Human MCC is a biotin dependent mitochondrial enzyme formed by the two subunits MCCCα and MCCCβ, encoded by MCCC1 and MCCC2 respectively.^[2] MCCC1 gene has 21 exons and resides on chromosome 3 at q27.^[3] MCCC2 gene has 19 exons and resides on chromosome 5 at q12-q13.^[4]

Protein

The enzyme contains α and β subunits. Human MCCCα is composed of 725 amino acids which harbor a covalently bound biotin essential for the ATP-dependent carboxylation; MCCCβ has 563 amino acids that possess carboxyltransferase activity which presumably is essential for binding to 3-methylcrotonyl CoA.^[5] The MCC holoenzyme is thought to be a heterododecamer (6α6β) with close structural analogy to propionyl-CoA carboxylase (PCC), another biotin dependent mitochondrial carboxylase.^[6]

Function

During branched-chain amino acid degradation, MCC performs a single step in the breakdown of leucine to eventually yield acetyl CoA and acetoacetate.^[7] MCC catalyzes the carboxylation of 3-methylcrotonyl CoA to 3-methylglutaconyl CoA, a critical step for leucine and isovaleric acid catabolism in species including mammals, plants and bacteria.^[8] 3-Methylglutaconyl CoA is then hydrated to produce 3-hydroxy-3-methylglutaryl CoA. 3-Hydroxy-3-methylglutaryl CoA is cleaved into two molecules, acetoacetate and acetyl CoA.

Point mutations and deletion events in the genes coding for MCC can lead to MCC deficiency, an inborn error of metabolism which usually presents with vomiting, metabolic acidosis, very low plasma glucose concentration, and very low levels of carnitine in plasma.^[9]

Leucine metabolism in humans

L-Leucine

Branched-chain amino
acid aminotransferase

Muscle: α-Ketoisocaproate (α-KIC)

Liver: α-Ketoisocaproate (α-KIC)

Branched-chain α-ketoacid
dehydrogenase (mitochondria)

KIC-dioxygenase
(cytosol)

Isovaleryl-CoA

β-Hydroxy
β-methylbutyrate
(HMB)

Excreted
in urine
(10–40%)

HMB-CoA

β-Hydroxy β-methylglutaryl-CoA
(HMG-CoA)

β-Methylcrotonyl-CoA
(MC-CoA)

β-Methylglutaconyl-CoA
(MG-CoA)

CO₂

O₂

CO₂

H₂O

CO₂

H₂O

(liver)
HMG-CoA
lyase

Enoyl-CoA hydratase

Isovaleryl-CoA
dehydrogenase

MC-CoA
carboxylase

MG-CoA
hydratase

HMG-CoA
reductase

HMG-CoA
synthase

β-Hydroxybutyrate
dehydrogenase

Unknown
enzyme

Human metabolic pathway for HMB and isovaleryl-CoA relative to L-leucine.^[10]^[11]^[12] Of the two major pathways, L-leucine is mostly metabolized into isovaleryl-CoA, while only about 5% is metabolized into HMB.^[10]^[11]^[12]

Mechanism

Bicarbonate is activated by the addition of ATP, increasing the reactivity of bicarbonate. Once bicarbonate is activated, the biotin portion of MCC performs nucleophilic attack on the activated bicarbonate to form enzyme-bound carboxybiotin. The carboxybiotin portion of MCC can then undergo nucleophilic attack transferring the carboxyl group to the substrate, 3-methylcrotonyl CoA, to form 3-methylglutaconyl CoA.^[7]

Regulation

MCC is covalently modified and inhibited by intermediates of leucine catabolism including 3-methylglutaconyl-CoA, 3-methylglutaryl-CoA, and 3-hydroxy-3-methylglutaryl-CoA that act as reactive acyl species on MCC in a negative feedback loop. SIRT4 activates MCC and upregulates leucine catabolism by removing acyl residues that modified MCC.^[13]

Clinical significance

In humans, MCC deficiency is a rare autosomal recessive genetic disorder whose clinical presentations range from benign to profound metabolic acidosis and death in infancy. Defective mutations in either the α or β subunit have been shown to cause the MCC-deficient syndrome.^[5] The typical diagnostic test is the elevated urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. Patients with MCC deficiency usually have normal growth and development before the first acute episode, such as convulsions or coma, that usually occurs between the age of 6-months to 3-years.^[14]

Interactions

MCC has been shown to interact with TRI6 in Fusarium graminearum.^[15]

References

^ Bruice PY (2001). Organic chemistry: study guide and solutions manual (2nd ed.). Upper Saddle River, N.J.: Prentice Hall. pp. 1010–11. ISBN 978-0-13-017859-6.
^ Morscher RJ, Grünert SC, Bürer C, Burda P, Suormala T, Fowler B, Baumgartner MR (Apr 2012). "A single mutation in MCCC1 or MCCC2 as a potential cause of positive screening for 3-methylcrotonyl-CoA carboxylase deficiency". Molecular Genetics and Metabolism. 105 (4): 602–6. doi:10.1016/j.ymgme.2011.12.018. PMID 22264772.
^ "Entrez Gene:MCCC1 methylcrotonoyl-CoA carboxylase 1".
^ "Entrez Gene:MCCC2 methylcrotonoyl-CoA carboxylase 2".
^ ^a ^b Holzinger A, Röschinger W, Lagler F, Mayerhofer PU, Lichtner P, Kattenfeld T, Thuy LP, Nyhan WL, Koch HG, Muntau AC, Roscher AA (Jun 2001). "Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency". Human Molecular Genetics. 10 (12): 1299–306. doi:10.1093/hmg/10.12.1299. PMID 11406611.
^ Huang CS, Sadre-Bazzaz K, Shen Y, Deng B, Zhou ZH, Tong L (Aug 2010). "Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme A carboxylase". Nature. 466 (7309): 1001–5. doi:10.1038/nature09302. PMC 2925307. PMID 20725044.
^ ^a ^b Berg JM, Tymoczko JL, Stryer L (2002). "Chapter 16.3.2: The Conversion of Pyruvate into Phosphoenolpyruvate Begins with the Formation of Oxaloacetate". Biochemistry (5th ed.). New York, NY: W. H. Freeman. pp. 652–3. ISBN 0-7167-3051-0.
^ Chu CH, Cheng D (Jun 2007). "Expression, purification, characterization of human 3-methylcrotonyl-CoA carboxylase (MCCC)". Protein Expression and Purification. 53 (2): 421–7. doi:10.1016/j.pep.2007.01.012. PMID 17360195.
^ Stipanuk MH (2000). Biochemical and physiological aspects of human nutrition. Philadelphia, Pa.: Saunders. pp. 535–6. ISBN 978-0-7216-4452-3.
^ ^a ^b Wilson JM, Fitschen PJ, Campbell B, Wilson GJ, Zanchi N, Taylor L, Wilborn C, Kalman DS, Stout JR, Hoffman JR, Ziegenfuss TN, Lopez HL, Kreider RB, Smith-Ryan AE, Antonio J (February 2013). "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". Journal of the International Society of Sports Nutrition. 10 (1): 6. doi:10.1186/1550-2783-10-6. PMC 3568064. PMID 23374455.
^ ^a ^b Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH (April 2011). "HMB supplementation: clinical and athletic performance-related effects and mechanisms of action". Amino Acids. 40 (4): 1015–1025. doi:10.1007/s00726-010-0678-0. PMID 20607321. S2CID 11120110. HMB is a metabolite of the amino acid leucine (Van Koverin and Nissen 1992), an essential amino acid. The first step in HMB metabolism is the reversible transamination of leucine to [α-KIC] that occurs mainly extrahepatically (Block and Buse 1990). Following this enzymatic reaction, [α-KIC] may follow one of two pathways. In the first, HMB is produced from [α-KIC] by the cytosolic enzyme KIC dioxygenase (Sabourin and Bieber 1983). The cytosolic dioxygenase has been characterized extensively and differs from the mitochondrial form in that the dioxygenase enzyme is a cytosolic enzyme, whereas the dehydrogenase enzyme is found exclusively in the mitochondrion (Sabourin and Bieber 1981, 1983). Importantly, this route of HMB formation is direct and completely dependent of liver KIC dioxygenase. Following this pathway, HMB in the cytosol is first converted to cytosolic β-hydroxy-β-methylglutaryl-CoA (HMG-CoA), which can then be directed for cholesterol synthesis (Rudney 1957) (Fig. 1). In fact, numerous biochemical studies have shown that HMB is a precursor of cholesterol (Zabin and Bloch 1951; Nissen et al. 2000).
^ ^a ^b Kohlmeier M (May 2015). "Leucine". Nutrient Metabolism: Structures, Functions, and Genes (2nd ed.). Academic Press. pp. 385–388. ISBN 978-0-12-387784-0. Retrieved 6 June 2016. Energy fuel: Eventually, most Leu is broken down, providing about 6.0kcal/g. About 60% of ingested Leu is oxidized within a few hours ... Ketogenesis: A significant proportion (40% of an ingested dose) is converted into acetyl-CoA and thereby contributes to the synthesis of ketones, steroids, fatty acids, and other compounds
Figure 8.57: Metabolism of L-leucine
^ Zaganjor E, Vyas S, Haigis MC (June 2017). "SIRT4 Is a Regulator of Insulin Secretion". Cell Chemical Biology. 24 (6): 656–658. doi:10.1016/j.chembiol.2017.06.002. PMID 28644956.
^ Baykal T, Gokcay GH, Ince Z, Dantas MF, Fowler B, Baumgartner MR, Demir F, Can G, Demirkol M (2005). "Consanguineous 3-methylcrotonyl-CoA carboxylase deficiency: early-onset necrotizing encephalopathy with lethal outcome". Journal of Inherited Metabolic Disease. 28 (2): 229–33. doi:10.1007/s10545-005-4559-8. PMID 15877210. S2CID 23446678.
^ Subramaniam R, Narayanan S, Walkowiak S, Wang L, Joshi M, Rocheleau H, Ouellet T, Harris LJ (Nov 2015). "Leucine metabolism regulates TRI6 expression and affects deoxynivalenol production and virulence in Fusarium graminearum". Molecular Microbiology. 98 (4): 760–9. doi:10.1111/mmi.13155. PMID 26248604. S2CID 29839939.