Biology:Methylcrotonyl-CoA carboxylase

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Short description: Class of enzymes


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example
Methylcrotonoyl-coenzyme A carboxylase 1 (alpha)
Identifiers
SymbolMCCC1
NCBI gene56922
HGNC6936
OMIM609010
RefSeqNM_020166
UniProtQ96RQ3
Other data
EC number6.4.1.4
LocusChr. 3 q27.1
Methylcrotonoyl-coenzyme A carboxylase 2 (beta)
Identifiers
SymbolMCCC2
NCBI gene64087
HGNC6937
OMIM609014
RefSeqNM_022132
UniProtQ9HCC0
Other data
EC number6.4.1.4
LocusChr. 5 q12-q13

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]

The image above contains clickable links
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

  1. ↑ Bruice, Paula Yurkanis (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. https://archive.org/details/organicchemistry00brui. 
  2. ↑ "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. Apr 2012. doi:10.1016/j.ymgme.2011.12.018. PMID 22264772. 
  3. ↑ "Entrez Gene:MCCC1 methylcrotonoyl-CoA carboxylase 1". https://www.ncbi.nlm.nih.gov/gene/56922. 
  4. ↑ "Entrez Gene:MCCC2 methylcrotonoyl-CoA carboxylase 2". https://www.ncbi.nlm.nih.gov/gene/64087. 
  5. ↑ 5.0 5.1 "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. Jun 2001. doi:10.1093/hmg/10.12.1299. PMID 11406611. 
  6. ↑ "Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme A carboxylase". Nature 466 (7309): 1001–5. Aug 2010. doi:10.1038/nature09302. PMID 20725044. 
  7. ↑ 7.0 7.1 Berg, Jeremy M.; Tymoczko, John L.; Stryer, Lubert (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. https://www.ncbi.nlm.nih.gov/books/NBK22591/#A2271. 
  8. ↑ "Expression, purification, characterization of human 3-methylcrotonyl-CoA carboxylase (MCCC)". Protein Expression and Purification 53 (2): 421–7. Jun 2007. doi:10.1016/j.pep.2007.01.012. PMID 17360195. 
  9. ↑ Stipanuk, Martha H. (2000). Biochemical and physiological aspects of human nutrition. Philadelphia, Pa.: Saunders. pp. 535–6. ISBN 978-0-7216-4452-3. 
  10. ↑ 10.0 10.1 "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". Journal of the International Society of Sports Nutrition 10 (1): 6. February 2013. doi:10.1186/1550-2783-10-6. PMID 23374455. 
  11. ↑ 12.0 12.1 Nutrient Metabolism: Structures, Functions, and Genes (2nd ed.). Academic Press. May 2015. pp. 385–388. ISBN 978-0-12-387784-0. https://books.google.com/books?id=aTQTAAAAQBAJ&printsec=frontcover#v=onepage. 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
  12. ↑ "SIRT4 Is a Regulator of Insulin Secretion". Cell Chemical Biology 24 (6): 656–658. June 2017. doi:10.1016/j.chembiol.2017.06.002. PMID 28644956. 
  13. ↑ "Consanguineous 3-methylcrotonyl-CoA carboxylase deficiency: early-onset necrotizing encephalopathy with lethal outcome". Journal of Inherited Metabolic Disease 28 (2): 229–33. 2005. doi:10.1007/s10545-005-4559-8. PMID 15877210. 
  14. ↑ "Leucine metabolism regulates TRI6 expression and affects deoxynivalenol production and virulence in Fusarium graminearum". Molecular Microbiology 98 (4): 760–9. Nov 2015. doi:10.1111/mmi.13155. PMID 26248604. 

External links



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