Methylcrotonyl-CoA carboxylase

Methylcrotonoyl-coenzyme A carboxylase 1 (alpha)
Identifiers
Symbol MCCC1
Entrez 56922
HUGO 6936
OMIM 609010
RefSeq NM_020166
UniProt Q96RQ3
Other data
EC number 6.4.1.4
Locus Chr. 3 q27.1
Methylcrotonoyl-coenzyme A carboxylase 2 (beta)
Identifiers
Symbol MCCC2
Entrez 64087
HUGO 6937
OMIM 609014
RefSeq NM_022132
UniProt Q9HCC0
Other data
EC number 6.4.1.4
Locus Chr. 5 q12-q13

Methylcrotonyl CoA carboxylase (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]

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 not regulated by small molecules or dietary or hormonal factors.[9]

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.[10]

Interactions

MCC has been shown to interact with TRI6 in Fusarium graminearum.[11]

References

  1. ↑ 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.
  2. ↑ 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. PMID 22264772. doi:10.1016/j.ymgme.2011.12.018.
  3. ↑ "Entrez Gene:MCCC1 methylcrotonoyl-CoA carboxylase 1".
  4. ↑ "Entrez Gene:MCCC2 methylcrotonoyl-CoA carboxylase 2".
  5. 1 2 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. PMID 11406611. doi:10.1093/hmg/10.12.1299.
  6. ↑ 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. PMC 2925307 Freely accessible. PMID 20725044. doi:10.1038/nature09302.
  7. 1 2 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.
  8. ↑ Chu CH, Cheng D (Jun 2007). "Expression, purification, characterization of human 3-methylcrotonyl-CoA carboxylase (MCCC)". Protein Expression and Purification. 53 (2): 421–7. PMID 17360195. doi:10.1016/j.pep.2007.01.012.
  9. 1 2 Stipanuk MH (2000). Biochemical and physiological aspects of human nutrition. Philadelphia, Pa.: Saunders. pp. 535–6. ISBN 978-0-7216-4452-3.
  10. ↑ 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. PMID 15877210. doi:10.1007/s10545-005-4559-8.
  11. ↑ 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. PMID 26248604. doi:10.1111/mmi.13155.
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