Methylmalonyl-CoA mutase

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MMUT
Protein MUT PDB 2XIJ.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases MMUT , MCM, methylmalonyl-CoA mutase, Methylmalonyl Coenzyme-A mutase, MUT
External IDs OMIM: 609058 MGI: 97239 HomoloGene: 20097 GeneCards: MMUT
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000255

NM_008650

RefSeq (protein)

NP_000246
NP_000246.2

NP_032676

Location (UCSC) Chr 6: 49.43 – 49.46 Mb Chr 17: 41.25 – 41.27 Mb
PubMed search [3] [4]
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methylmalonyl-CoA mutase
Identifiers
EC no. 5.4.99.2
CAS no. 9023-90-9
Databases
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BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
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PMC articles
PubMed articles
NCBI proteins

Methylmalonyl-CoA mutase (EC 5.4.99.2, MCM), mitochondrial, also known as methylmalonyl-CoA isomerase, is a protein that in humans is encoded by the MUT gene. This vitamin B12-dependent enzyme catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA in humans. Mutations in MUT gene may lead to various types of methylmalonic aciduria. [5]

Contents

MCM was first identified in rat liver and sheep kidney in 1955. In its latent form, it is 750 amino acids in length. Upon entry to the mitochondria, the 32 amino acid mitochondrial leader sequence at the N-terminus of the protein is cleaved, forming the fully processed monomer. The monomers then associate into homodimers, and bind AdoCbl (one for each monomer active site) to form the final, active holoenzyme form. [6]

Structure

Gene

The MUT gene lies on the chromosome location of 6p12.3 and consists of 13 exons, spanning over 35kb. [7]

Protein

The mature enzyme is a homodimer with the N-terminal CoA binding domain and the C- terminal cobalamin-binding domain. [8]

Function

Methylmalonyl-CoA mutase is expressed in high concentrations in the kidney, in intermediate concentrations in the heart, ovaries, brain, muscle, and liver, and in low concentrations in the spleen. [6] The enzyme can be found all throughout the central nervous system (CNS). [6] MCM resides in the mitochondria, where a number of substances, including the branched-chain amino acids isoleucine and valine, as well as methionine, threonine, thymine and odd-chain fatty acids, are metabolized via methylmalonate semialdehyde (MMlSA) or propionyl-CoA (Pr-CoA) to a common compound - methylmalonyl-CoA (MMl-CoA). MCM catalyzes the reversible isomerisation of l‐methylmalonyl‐CoA to succinyl‐CoA, requiring cobalamin (vitamin B12) in the form of adenosylcobalamin (AdoCbl) as a cofactor. As an important step in propionate catabolism, this reaction is required for the degradation of odd-chain fatty acids, the amino acids valine, isoleucine, methionine, and threonine, and cholesterol, [9] funneling metabolites from the breakdown of these amino acids into the tricarboxylic acid cycle. [10]

Methylmalonyl-CoA mutase catalyzes the following reaction:

L-methylmalonyl-CoA methylmalonyl-CoA mutase Succinyl-CoA
L-methylmalonyl-CoA.png   Succinyl-CoA.png
Biochem reaction arrow reversible NNNN horiz med.svg
 
 methylmalonyl-CoA mutase

The substrate of methylmalonyl-CoA mutase, methylmalonyl-CoA, is primarily derived from propionyl-CoA, a substance formed from the catabolism and digestion of isoleucine, valine, threonine, methionine, thymine, cholesterol, or odd-chain fatty acids. The product of the enzyme, succinyl-CoA, is a key molecule of the tricarboxylic acid cycle.

Clinical significance

A deficiency of this enzyme is responsible for an inherited disorder of metabolism, methylmalonyl-CoA mutase deficiency, which is one of the causes of methylmalonic acidemia (also referred to as methylmalonic aciduria or MMA). MMA is an autosomal recessive inherited inborn error of metabolism, characterized by recurrent episodes of vomiting, lethargy, profound ketoacidosis, hyperammonemia, and pancytopenia in infancy, and may cause early death. Complications include cardiomyopathy, metabolic stroke, pancreatitis, and progressive renal failure. [5] [11]

Either mutations to the gene MUT (encodes methylmalonyl-CoA mutase), or MMAA (encodes a chaperone protein of methylmalonyl-CoA mutase, MMAA protein) can lead to methylmalonyl acidemia. [12] Mutations to MUT can be categorized as either MUT0 (demonstrates no activity even in presence of excess AdoCbl), or MUT1 (demonstrates very low activity in presence of excess AdoCbl). [8] Over half of the mutations of MUT are missense mutations [10] while nonsense mutations comprise a significant remaining fraction (approximately 14%) [13]

Common treatment methods for MMA include a liver transplant or a liver and kidney transplant to combat the renal disease of methylmalonic acidemia. However, detrimental neurological effects can continue to plague patients even after a successful operation. It is thought that this is due to the widespread presence of methylmalonyl-CoA mutase throughout the central nervous system. Due to the loss of functionality of the enzyme, substrate levels build up in the CNS. The substrate, L-methylmalonyl-CoA hydrolyzes to form methylmalonate (methylmalonic acid), a neurotoxic dicarboxylic acid that, due to the poor dicarboxylic acid transport capacities of the blood-brain barrier, is effectively trapped within the CNS, leading to neurological debilitation. To combat these effects perioperative anti-catabolic regimes and no diet discontinuation are recommended. [6]

The murine model has proven an adequate and accurate way of studying the effects of MMA, and potential treatment methods. [14] [15]

Mechanism

MCM's reaction mechanism MUT.png
MCM's reaction mechanism

The MCM reaction mechanism begins with homolytic cleavage of AdoB12's C-Co(III) bond, the C and Co atoms each acquire one of the electrons that formed the cleaved electron pair bond. The Co ion, therefore, fluctuates between its Co(III) and Co(II) oxidation states [the two states are spectroscopically distinguishable: Co(III) is red and diamagnetic (no unpaired electrons), whereas Co(II) is yellow and paramagnetic (unpaired electrons)]. Hence, the role of coenzyme B-12 in the catalytic process is that of a reversible generator of a free radical. The C-Co(III) bond is weak, with a dissociation energy = 109 kJ/mol, and appears to be further weakened through steric interactions with the enzyme. The homolytic reaction is unusual in biology, as is the presence of a metal-carbon bond.

Methylmalonyl-CoA mutase is a member of the isomerase subfamily of adenosylcobalamin-dependent enzymes. Furthermore, it is classified as class I, as it is a ‘DMB-off’/’His-on’ enzyme. This refers to the nature of the AdoCbl cofactor in the active site of methylmalonyl CoA. [16] AdoCbl is composed of a central cobalt-containing corrin ring, an upper axial ligand (β-axial ligand), and a lower axial ligand (α-axial ligand). In methylmalonyl-CoA mutase, the β-axial ligand 5’-deoxy-5’-adenosine reversibly dissociated to give the deoxyadenosyl radical. The α-axial ligand 5,6-dimethylbenzimidazole (DMB) is involved in organizing the active site to enable histidine-610 to bond with Co, instead of DMB (the reason for the ‘DMB-off’/’His-on’ notation). [16] Binding of histidine-610 residue increases the rate of homolytic β-axial ligand – Co bond breakage by a factor of 1012. [17]

MCM active site. Corrin ring and a-axial ligand (DMB): (yellow), b-axial ligand: (green), substrate/product: (cyan), residues interacting with b-axial ligand: glu370, asn366, gly91, ala139 (blue), residues interacting with substrate: gln197, his244, arg207, tyr89 (red), and his610: (orange). Rendered from PDB 4REQ. Active site MCM colors.png
MCM active site. Corrin ring and α-axial ligand (DMB): (yellow), β-axial ligand: (green), substrate/product: (cyan), residues interacting with β-axial ligand: glu370, asn366, gly91, ala139 (blue), residues interacting with substrate: gln197, his244, arg207, tyr89 (red), and his610: (orange). Rendered from PDB 4REQ.

Other important residues of methylmalonyl-CoA mutase include Histidine-244, which acts as a general acid near the substrate and shields the radical species from side reactions involving oxygen, [20] Glutamate-370, whose hydrogen bond with the 2’-OH group of the ribose of the β-axial ligand forces interaction between the β-axial ligand radical species and the substrate, [21] and tyrosine-89 which stabilizes reactive radical intermediates and accounts for the stereo-selectivity of the enzyme. [18] [22]

The processing protein, MMAA protein, fills the important role of aiding cofactor loading and exchange. [12] [23] MMAA protein favors association with the MCM apoenzyme, and allows for the transfer of the AdoCbl cofactor to the enzyme active site. [23] Furthermore, if the bound AdoCbl accrues oxidative damage during normal functioning, MMAA protein fosters exchange of the damaged cofactor for a new AdoCbl via a GTP-reliant pathway. [12] [23]

Interactions

Related Research Articles

<span class="mw-page-title-main">Threonine</span> Amino acid

Threonine is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group, a carboxyl group, and a side chain containing a hydroxyl group, making it a polar, uncharged amino acid. It is essential in humans, meaning the body cannot synthesize it: it must be obtained from the diet. Threonine is synthesized from aspartate in bacteria such as E. coli. It is encoded by all the codons starting AC.

<span class="mw-page-title-main">Methylmalonic acidemia</span> Medical condition

Methylmalonic acidemia, also called methylmalonic aciduria, is an autosomal recessive metabolic disorder that disrupts normal amino acid metabolism. It is a classical type of organic acidemia. The result of this condition is the inability to properly digest specific fats and proteins, which in turn leads to a buildup of a toxic level of methylmalonic acid in the blood.

Propionic acidemia, also known as propionic aciduria or propionyl-CoA carboxylase deficiency, is a rare autosomal recessive metabolic disorder, classified as a branched-chain organic acidemia.

<span class="mw-page-title-main">Isovaleric acidemia</span> Medical condition disrupting normal metabolism

Isovaleric acidemia is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine. It is a classical type of organic acidemia.

<span class="mw-page-title-main">Methylmalonyl-CoA mutase deficiency</span> Medical condition

Methylmalonyl-CoA mutase is a mitochondrial homodimer apoenzyme that focuses on the catalysis of methylmalonyl CoA to succinyl CoA. The enzyme is bound to adenosylcobalamin, a hormonal derivative of vitamin B12 in order to function. Methylmalonyl-CoA mutase deficiency is caused by genetic defect in the MUT gene responsible for encoding the enzyme. Deficiency in this enzyme accounts for 60% of the cases of methylmalonic acidemia.

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">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">Methylmalonic acid</span> Chemical compound

Methylmalonic acid (MMA) is a dicarboxylic acid that is a C-methylated derivative of malonic acid.

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

Methylmalonyl-CoA is the thioester consisting of coenzyme A linked to methylmalonic acid. It is an important intermediate in the biosynthesis of succinyl-CoA, which plays an essential role in the tricarboxylic acid cycle. The compound is sometimes referred to as "methylmalyl-CoA".

<span class="mw-page-title-main">Methylmalonyl CoA epimerase</span>

Methylmalonyl CoA epimerase is an enzyme involved in fatty acid catabolism that is encoded in human by the "MCEE" gene located on chromosome 2. It is routinely and incorrectly labeled as "methylmalonyl-CoA racemase". It is not a racemase because the CoA moiety has 5 other stereocenters.

<span class="mw-page-title-main">Adenosylcobalamin</span> Biologically active form of vitamin B12

Adenosylcobalamin (AdoCbl), also known as coenzyme B12, cobamamide, and dibencozide, is, along with methylcobalamin (MeCbl), one of the biologically active forms of vitamin B12.

<span class="mw-page-title-main">Cobalamin riboswitch</span>

Cobalamin riboswitch is a cis-regulatory element which is widely distributed in 5' untranslated regions of vitamin B12 (Cobalamin) related genes in bacteria.

<span class="mw-page-title-main">Cyanocobalamin</span> Form of vitamin B-12

Cyanocobalamin is a form of vitamin B
12
used to treat vitamin B
12
deficiency
except in the presence of cyanide toxicity. The deficiency may occur in pernicious anemia, following surgical removal of the stomach, with fish tapeworm, or due to bowel cancer. It is less preferred than hydroxocobalamin for treating vitamin B
12
deficiency. Some study have shown that it has an antihypotensive effect. It is used by mouth, by injection into a muscle, or as a nasal spray.

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

Cob(I)yrinic acid a,c-diamide adenosyltransferase, mitochondrial is an enzyme that in humans is encoded by the MMAB gene.

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

Methylmalonic aciduria type A protein, mitochondrial also known as MMAA is a protein that in humans is encoded by the MMAA gene.

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

Methylmalonic aciduria and homocystinuria type C protein (MMACHC) is a protein that in humans is encoded by the MMACHC gene.

<span class="mw-page-title-main">MMADHC</span> Protein-coding gene in humans

Methylmalonic aciduria and homocystinuria type D protein, mitochondrial also known as MMADHC is a protein that in humans is encoded by the MMADHC gene.

<span class="mw-page-title-main">Imerslund–Gräsbeck syndrome</span> Medical condition

Imerslund–Gräsbeck syndrome is a rare autosomal recessive, familial form of vitamin B12 deficiency caused by malfunction of the "Cubam" receptor located in the terminal ileum. This receptor is composed of two proteins, amnionless (AMN), and cubilin. A defect in either of these protein components can cause this syndrome. This is a rare disease, with a prevalence about 1 in 200,000, and is usually seen in patients of European ancestry.

Combined malonic and methylmalonic aciduria (CMAMMA), also called combined malonic and methylmalonic acidemia is an inherited metabolic disease characterized by elevated levels of malonic acid and methylmalonic acid. Some researchers have hypothesized that CMAMMA might be one of the most common forms of methylmalonic acidemia, and possibly one of the most common inborn errors of metabolism. Due to being infrequently diagnosed, it most often goes undetected.

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Further reading