Methylmalonyl-CoA - Misplaced Pages

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Methylmalonyl-CoA
Names

Systematic IUPAC name (9R)-1--3,5,9-trihydroxy-8,8,20-trimethyl-3,5,10,14,19-pentaoxo-2,4,6-trioxa-18-thia-11,15-diaza-3λ,5λ-diphosphahenicosan-21-oic acid
Identifiers
CAS Number	1264-45-5
3D model (JSmol)	Interactive image
ChEBI	CHEBI:16625
ChemSpider	110440
IUPHAR/BPS	5223
PubChem CID	123909
CompTox Dashboard (EPA)	DTXSID20925529
InChI InChI=1S/C25H40N7O19P3S/c1-12(23(37)38)24(39)55-7-6-27-14(33)4-5-28-21(36)18(35)25(2,3)9-48-54(45,46)51-53(43,44)47-8-13-17(50-52(40,41)42)16(34)22(49-13)32-11-31-15-19(26)29-10-30-20(15)32/h10-13,16-18,22,34-35H,4-9H2,1-3H3,(H,27,33)(H,28,36)(H,37,38)(H,43,44)(H,45,46)(H2,26,29,30)(H2,40,41,42)/t12?,13-,16-,17-,18+,22-/m1/s1Key: MZFOKIKEPGUZEN-FBMOWMAESA-N InChI=1/C25H40N7O19P3S/c1-12(23(37)38)24(39)55-7-6-27-14(33)4-5-28-21(36)18(35)25(2,3)9-48-54(45,46)51-53(43,44)47-8-13-17(50-52(40,41)42)16(34)22(49-13)32-11-31-15-19(26)29-10-30-20(15)32/h10-13,16-18,22,34-35H,4-9H2,1-3H3,(H,27,33)(H,28,36)(H,37,38)(H,43,44)(H,45,46)(H2,26,29,30)(H2,40,41,42)/t12?,13-,16-,17-,18+,22-/m1/s1Key: MZFOKIKEPGUZEN-FBMOWMAEBZ
SMILES CC(C(=O)O)C(=O)SCCNC(=O)CCNC(=O)(C(C)(C)COP(=O)(O)OP(=O)(O)OC1(((O1)N2C=NC3=C(N=CN=C32)N)O)OP(=O)(O)O)O
Properties
Chemical formula	C₂₅H₄₀N₇O₁₉P₃S
Molar mass	867.608 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C , 100 kPa). N verify (what is ?) Infobox references

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 (aka the Citric Acid Cycle, or Krebs Cycle).

Biosynthesis and metabolism

Methylmalonyl-CoA results from the metabolism of fatty acid with an odd number of carbons, of amino acids valine, isoleucine, methionine, threonine or of cholesterol side-chains, forming Propionyl-CoA. The latter is also formed from propionic acid, which bacteria produce in the intestine. Propionyl-CoA and bicarbonate are converted to Methylmalonyl-CoA by the enzyme propionyl-CoA Carboxylase. It then is converted into succinyl-CoA by methylmalonyl-CoA mutase (MUT). This reaction is a reversible isomerization. In this way, the compound enters the Citric Acid Cycle. The following diagram demonstrates the aforementioned reaction:

Propionyl CoA + Bicarbonate → Methylmalonyl CoA → Succinyl CoA

Vitamin B₁₂

Vitamin B₁₂ plays an integral role in this reaction. Coenzyme B₁₂ (adenosyl-cobalamin) is an organometallic form of Vitamin B₁₂ and serves as the cofactor of Methylmalonyl-CoA mutase, which is an essential enzyme in the human body. The transformation of Methylmalonyl-CoA to Succinyl-CoA by this enzyme is a radical reaction.

Related diseases

Methylmalonic Acidemia (MMA)

Main article: Methylmalonyl-CoA mutase deficiency

This disease occurs when methylmalonyl-CoA mutase is unable to isomerize sufficient amounts of methylmalonyl-CoA into succinyl-CoA. This causes a buildup of propionic and/or methylmalonic acid, which has effects on infants ranging from severe brain damage to death. The disease is linked to Vitamin B₁₂, which is a cofactor for the enzyme methylmalonyl-CoA mutase.

Combined malonic and methylmalonic aciduria (CMAMMA)

In the metabolic disease combined malonic and methylmalonic aciduria (CMAMMA), acyl-CoA synthetase family member 3 (ACSF3) is reduced, which converts toxic methylmalonic acid to methylmalonyl-CoA and thus supplies it to the citric acid cycle. The result is an accumulation of methylmalonic acid.

References

^ Wongkittichote P, Ah Mew N, Chapman KA (December 2017). "Propionyl-CoA carboxylase - A review". Molecular Genetics and Metabolism. 122 (4): 145–152. doi:10.1016/j.ymgme.2017.10.002. PMC 5725275. PMID 29033250.
^ Baumgartner MR, Hörster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, et al. (September 2014). "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia". Orphanet Journal of Rare Diseases. 9 (1): 130. doi:10.1186/s13023-014-0130-8. PMC 4180313. PMID 25205257.
Nelson DL, Cox MM (2005). Principles of Biochemistry (4th ed.). New York: W. H. Freeman. ISBN 0-7167-4339-6.
^ Kräutler B (2012). "Biochemistry of B12-cofactors in human metabolism". In Stanger O (ed.). Water Soluble Vitamins. Subcellular Biochemistry. Vol. 56. Dordrecht: Springer Netherlands. pp. 323–346. doi:10.1007/978-94-007-2199-9_17. ISBN 978-94-007-2198-2. PMID 22116707.
^ Takahashi-Iñiguez T, García-Hernandez E, Arreguín-Espinosa R, Flores ME (June 2012). "Role of vitamin B12 on methylmalonyl-CoA mutase activity". Journal of Zhejiang University. Science. B. 13 (6): 423–437. doi:10.1631/jzus.B1100329. PMC 3370288. PMID 22661206.
Froese DS, Fowler B, Baumgartner MR (July 2019). "Vitamin B₁₂ , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation". Journal of Inherited Metabolic Disease. 42 (4): 673–685. doi:10.1002/jimd.12009. PMID 30693532.
Gabriel MC, Rice SM, Sloan JL, Mossayebi MH, Venditti CP, Al-Kouatly HB (April 2021). "Considerations of expanded carrier screening: Lessons learned from combined malonic and methylmalonic aciduria". Molecular Genetics & Genomic Medicine. 9 (4): e1621. doi:10.1002/mgg3.1621. PMC 8123733. PMID 33625768.
Bowman CE, Wolfgang MJ (January 2019). "Role of the malonyl-CoA synthetase ACSF3 in mitochondrial metabolism". Advances in Biological Regulation. 71: 34–40. doi:10.1016/j.jbior.2018.09.002. PMC 6347522. PMID 30201289.

Amino acid metabolism metabolic intermediates

K→acetyl-CoA

lysine→	Saccharopine Allysine α-Aminoadipic acid 2-Oxoadipic acid Glutaryl-CoA Glutaconyl-CoA Crotonyl-CoA β-Hydroxybutyryl-CoA
leucine→	β-Hydroxy β-methylbutyric acid β-Hydroxy β-methylbutyryl-CoA Isovaleryl-CoA α-Ketoisocaproic acid β-Ketoisocaproic acid β-Ketoisocaproyl-CoA β-Leucine β-Methylcrotonyl-CoA β-Methylglutaconyl-CoA β-Hydroxy β-methylglutaryl-CoA
tryptophan→alanine→	N′-Formylkynurenine Kynurenine Anthranilic acid 3-Hydroxykynurenine 3-Hydroxyanthranilic acid 2-Amino-3-carboxymuconic semialdehyde 2-Aminomuconic semialdehyde 2-Aminomuconic acid Glutaryl-CoA

G→pyruvate→
citrate

glycine→
serine→

3-Phosphoglyceric acid

G→glutamate→
α-ketoglutarate

histidine→	Urocanic acid Imidazol-4-one-5-propionic acid Formiminoglutamic acid Glutamate-1-semialdehyde
proline→	1-Pyrroline-5-carboxylic acid
arginine→	Agmatine Ornithine Citrulline Cadaverine Putrescine
other	cysteine+glutamate→glutathione: γ-Glutamylcysteine

G→propionyl-CoA→
succinyl-CoA

valine→	α-Ketoisovaleric acid Isobutyryl-CoA Methacrylyl-CoA 3-Hydroxyisobutyryl-CoA 3-Hydroxyisobutyric acid 2-Methyl-3-oxopropanoic acid
isoleucine→	2,3-Dihydroxy-3-methylpentanoic acid 2-Methylbutyryl-CoA Tiglyl-CoA 2-Methylacetoacetyl-CoA
methionine→	generation of homocysteine: S-Adenosyl methionine S-Adenosyl-L-homocysteine Homocysteine conversion to cysteine: Cystathionine α-Ketobutyric acid + Cysteine
threonine→	α-Ketobutyric acid
propionyl-CoA→	Methylmalonyl-CoA

G→fumarate

phenylalanine→tyrosine→	4-Hydroxyphenylpyruvic acid Homogentisic acid 4-Maleylacetoacetic acid

G→oxaloacetate

see urea cycle

Other

Cysteine metabolism	Cysteine sulfinic acid

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