Methylcrotonyl-CoA carboxylase

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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:
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human
Methylcrotonoyl-coenzyme A carboxylase 1 (alpha)
Identifiers
SymbolMCCC1
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
Methylcrotonoyl-coenzyme A carboxylase 2 (beta)
Identifiers
SymbolMCCC2
NCBI gene 64087
HGNC 6937
OMIM 609014
RefSeq NM_022132
UniProt Q9HCC0
Other data
EC number 6.4.1.4
Locus Chr. 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]

Contents

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 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]

Related Research Articles

<span class="mw-page-title-main">Biotin</span> Chemical compound (vitamin B7)

Biotin (or vitamin B7) is one of the B vitamins. It is involved in a wide range of metabolic processes, both in humans and in other organisms, primarily related to the utilization of fats, carbohydrates, and amino acids. The name biotin derives from the Greek word "bios" (to live) and the suffix "-in" (a suffix used in chemistry usually to indicate "forming").

<span class="mw-page-title-main">Leucine</span> Chemical compound

Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO− form under biological conditions), and a side chain isobutyl group, making it a non-polar aliphatic amino acid. It is essential in humans, meaning the body cannot synthesize it: it must be obtained from the diet. Human dietary sources are foods that contain protein, such as meats, dairy products, soy products, and beans and other legumes. It is encoded by the codons UUA, UUG, CUU, CUC, CUA, and CUG.

<i>beta</i>-Hydroxy <i>beta</i>-methylbutyric acid Chemical compound

β-Hydroxy β-methylbutyric acid (HMB), otherwise known as its conjugate base, β-hydroxyβ-methylbutyrate, is a naturally produced substance in humans that is used as a dietary supplement and as an ingredient in certain medical foods that are intended to promote wound healing and provide nutritional support for people with muscle wasting due to cancer or HIV/AIDS. In healthy adults, supplementation with HMB has been shown to increase exercise-induced gains in muscle size, muscle strength, and lean body mass, reduce skeletal muscle damage from exercise, improve aerobic exercise performance, and expedite recovery from exercise. Medical reviews and meta-analyses indicate that HMB supplementation also helps to preserve or increase lean body mass and muscle strength in individuals experiencing age-related muscle loss. HMB produces these effects in part by stimulating the production of proteins and inhibiting the breakdown of proteins in muscle tissue. No adverse effects from long-term use as a dietary supplement in adults have been found.

<span class="mw-page-title-main">Biotinidase deficiency</span> Medical condition

Biotinidase deficiency is an autosomal recessive metabolic disorder in which biotin is not released from proteins in the diet during digestion or from normal protein turnover in the cell. This situation results in biotin deficiency.

<span class="mw-page-title-main">3-Methylcrotonyl-CoA carboxylase deficiency</span> Medical condition

3-Methylcrotonyl-CoA carboxylase deficiency also known as 3-Methylcrotonylglycinuria or BMCC deficiency is an inherited disorder in which the body is unable to process certain proteins properly. People with this disorder have inadequate levels of an enzyme that helps break down proteins containing the amino acid leucine. This condition affects an estimated 1 in 50,000 individuals worldwide.

<i>beta</i>-Hydroxybutyric acid Chemical compound

β-Hydroxybutyric acid, also known as 3-hydroxybutyric acid or BHB, is an organic compound and a beta hydroxy acid with the chemical formula CH3CH(OH)CH2CO2H; its conjugate base is β-hydroxybutyrate, also known as 3-hydroxybutyrate. β-Hydroxybutyric acid is a chiral compound with two enantiomers: D-β-hydroxybutyric acid and L-β-hydroxybutyric acid. Its oxidized and polymeric derivatives occur widely in nature. In humans, D-β-hydroxybutyric acid is one of two primary endogenous agonists of hydroxycarboxylic acid receptor 2 (HCA2), a Gi/o-coupled G protein-coupled receptor (GPCR).

<span class="mw-page-title-main">HMG-CoA</span> Chemical compound

β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl coenzyme A, is an intermediate in the mevalonate and ketogenesis pathways. It is formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase. The research of Minor J. Coon and Bimal Kumar Bachhawat in the 1950s at University of Illinois led to its discovery.

Propionyl-CoA is a coenzyme A derivative of propionic acid. It is composed of a 24 total carbon chain and its production and metabolic fate depend on which organism it is present in. Several different pathways can lead to its production, such as through the catabolism of specific amino acids or the oxidation of odd-chain fatty acids. It later can be broken down by propionyl-CoA carboxylase or through the methylcitrate cycle. In different organisms, however, propionyl-CoA can be sequestered into controlled regions, to alleviate its potential toxicity through accumulation. Genetic deficiencies regarding the production and breakdown of propionyl-CoA also have great clinical and human significance.

<span class="mw-page-title-main">Enoyl-CoA hydratase</span>

Enoyl-CoA hydratase (ECH) or crotonase is an enzyme EC 4.2.1.17 that hydrates the double bond between the second and third carbons on 2-trans/cis-enoyl-CoA:

<span class="mw-page-title-main">Propionyl-CoA carboxylase</span>

Propionyl-CoA carboxylase (EC 6.4.1.3, PCC) catalyses the carboxylation reaction of propionyl-CoA in the mitochondrial matrix. PCC has been classified both as a ligase and a lyase. The enzyme is biotin-dependent. The product of the reaction is (S)-methylmalonyl CoA.

<span class="mw-page-title-main">3-Hydroxy-3-methylglutaryl-CoA lyase</span> Class of enzymes

3-Hydroxy-3-methylglutaryl-CoA lyase is an enzyme (EC 4.1.3.4 that in human is encoded by the HMGCL gene located on chromosome 1. It is a key enzyme in ketogenesis. It is a ketogenic enzyme in the liver that catalyzes the formation of acetoacetate from HMG-CoA within the mitochondria. It also plays a prominent role in the catabolism of the amino acid leucine.

<span class="mw-page-title-main">Isovaleryl-CoA</span> Chemical compound

Isovaleryl-coenzyme A, also known as isovaleryl-CoA, is an intermediate in the metabolism of branched-chain amino acids.

<span class="mw-page-title-main">Methylcrotonyl-CoA</span> Chemical compound

3-Methylcrotonyl-CoA or β-Methylcrotonyl-CoA is an intermediate in the metabolism of leucine.

<span class="mw-page-title-main">3-Methylglutaconyl-CoA</span> Chemical compound

3-Methylglutaconyl-CoA (MG-CoA), also known as β-methylglutaconyl-CoA, is an intermediate in the metabolism of leucine. It is metabolized into HMG-CoA.

<span class="mw-page-title-main">Methylglutaconyl-CoA hydratase</span> Protein-coding gene in the species Homo sapiens

3-Methylglutaconyl-CoA hydratase, also known as MG-CoA hydratase and AUH, is an enzyme encoded by the AUH gene on chromosome 19. It is a member of the enoyl-CoA hydratase/isomerase superfamily, but it is the only member of that family that is able to bind to RNA. Not only does it bind to RNA, AUH has also been observed to be involved in the metabolic enzymatic activity, making it a dual-role protein. Mutations of this gene have been found to cause a disease called 3-Methylglutaconic Acuduria Type 1.

<span class="mw-page-title-main">Isovaleryl-CoA dehydrogenase</span>

In enzymology, an isovaleryl-CoA dehydrogenase is an enzyme that catalyzes the chemical reaction

In enzymology, a biotin-[methylcrotonoyl-CoA-carboxylase] ligase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Hydroxymethylglutaryl-CoA synthase</span> Class of enzymes

In molecular biology, hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase EC 2.3.3.10 is an enzyme which catalyzes the reaction in which acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This reaction comprises the second step in the mevalonate-dependent isoprenoid biosynthesis pathway. HMG-CoA is an intermediate in both cholesterol synthesis and ketogenesis. This reaction is overactivated in patients with diabetes mellitus type 1 if left untreated, due to prolonged insulin deficiency and the exhaustion of substrates for gluconeogenesis and the TCA cycle, notably oxaloacetate. This results in shunting of excess acetyl-CoA into the ketone synthesis pathway via HMG-CoA, leading to the development of diabetic ketoacidosis.

<i>alpha</i>-Ketoisocaproic acid Chemical compound

α-Ketoisocaproic acid (α-KIC) and its conjugate base, α-ketoisocaproate, are metabolic intermediates in the metabolic pathway for L-leucine. Leucine is an essential amino acid, and its degradation is critical for many biological duties. α-KIC is produced in one of the first steps of the pathway by branched-chain amino acid aminotransferase by transferring the amine on L-leucine onto alpha ketoglutarate, and replacing that amine with a ketone. The degradation of L-leucine in the muscle to this compound allows for the production of the amino acids alanine and glutamate as well. In the liver, α-KIC can be converted to a vast number of compounds depending on the enzymes and cofactors present, including cholesterol, acetyl-CoA, isovaleryl-CoA, and other biological molecules. Isovaleryl-CoA is the main compound synthesized from ɑ-KIC. α-KIC is a key metabolite present in the urine of people with Maple syrup urine disease, along with other branched-chain amino acids. Derivatives of α-KIC have been studied in humans for their ability to improve physical performance during anaerobic exercise as a supplemental bridge between short-term and long-term exercise supplements. These studies show that α-KIC does not achieve this goal without other ergogenicsupplements present as well. α-KIC has also been observed to reduce skeletal muscle damage after eccentrically biased resistance exercises in people who do not usually perform those exercises.

<i>beta</i>-Hydroxy <i>beta</i>-methylbutyryl-CoA Chemical compound

β-Hydroxy β-methylbutyryl-coenzyme A (HMB-CoA), also known as 3-hydroxyisovaleryl-CoA, is a metabolite of L-leucine that is produced in the human body. Its immediate precursors are β-hydroxy β-methylbutyric acid (HMB) and β-methylcrotonoyl-CoA (MC-CoA). It can be metabolized into HMB, MC-CoA, and HMG-CoA in humans.

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. doi:10.1016/j.ymgme.2011.12.018. PMID   22264772.
  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. doi: 10.1093/hmg/10.12.1299 . PMID   11406611.
  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. doi:10.1038/nature09302. PMC   2925307 . PMID   20725044.
  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. doi:10.1016/j.pep.2007.01.012. PMID   17360195.
  9. ↑ Stipanuk MH (2000). Biochemical and physiological aspects of human nutrition. Philadelphia, Pa.: Saunders. pp. 535–6. ISBN   978-0-7216-4452-3.
  10. 1 2 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.
  11. 1 2 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
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
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