Methylmalonyl-CoA: Difference between revisions

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 431161699

| ImageFile = Methylmalonyl-CoA.svg

| SystematicName = (9''R'')-1-[(2''R'',3''S'',4''R'',5''R'')-5-(6-Amino-9''H''-purin-9-yl)-4-hydroxy-3-(phosphonooxy)oxolan-2-yl]-3,5,9-trihydroxy-8,8,20-trimethyl-3,5,10,14,19-pentaoxo-2,4,6-trioxa-18-thia-11,15-diaza-3λ⁵,5λ⁵-diphosphahenicosan-21-oic acid

|Section1={{Chembox Identifiers

| IUPHAR_ligand = 5223

| CASNo_Ref = {{cascite|correct|??}}

| CASNo = 1264-45-5

| PubChem = 123909

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 110440| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 16625

| SMILES = CC(C(=O)O)C(=O)SCCNC(=O)CCNC(=O)[C@@H](C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=NC3=C(N=CN=C32)N)O)OP(=O)(O)O)O

| 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/s1

| InChIKey = MZFOKIKEPGUZEN-FBMOWMAEBZ

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 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/s1

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = MZFOKIKEPGUZEN-FBMOWMAESA-N

|Section2={{Chembox Properties

| Formula = C₂₅H₄₀N₇O₁₉P₃S

| MolarMass = 867.608 g/mol

| Appearance =

| Density =

| MeltingPt =

| BoilingPt =

| Solubility =

|Section3={{Chembox Hazards

| MainHazards =

| FlashPt =

| AutoignitionPt =

}}'''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|Citric Acid Cycle, or Krebs Cycle]]).<ref name="Wongkittichote_2017">{{cite journal | vauthors = Wongkittichote P, Ah Mew N, Chapman KA | title = Propionyl-CoA carboxylase - A review | journal = Molecular Genetics and Metabolism | volume = 122 | issue = 4 | pages = 145–152 | date = December 2017 | pmid = 29033250 | pmc = 5725275 | doi = 10.1016/j.ymgme.2017.10.002 }}</ref>

== Biosynthesis and metabolism ==

[[File:Propionate pathway.svg|left|thumb|Methylmalonyl-CoA pathway]]

Methylmalonyl-CoA results from the [[metabolism]] of [[fatty acid]] with an [[Parity (mathematics)|odd number]] of [[Carbon|carbons]], of [[Amino acid|amino acids]] [[valine]], [[isoleucine]], [[methionine]], [[threonine]] or of [[Cholesterol|cholesterol side-chains]], forming [[Propionyl-CoA]].<ref name="Baumgartner_2014">{{cite journal | vauthors = Baumgartner MR, Hörster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, Huemer M, Hochuli M, Assoun M, Ballhausen D, Burlina A, Fowler B, Grünert SC, Grünewald S, Honzik T, Merinero B, Pérez-Cerdá C, Scholl-Bürgi S, Skovby F, Wijburg F, MacDonald A, Martinelli D, Sass JO, Valayannopoulos V, Chakrapani A | display-authors = 6 | title = Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia | journal = Orphanet Journal of Rare Diseases | volume = 9 | issue = 1 | pages = 130 | date = September 2014 | pmid = 25205257 | pmc = 4180313 | doi = 10.1186/s13023-014-0130-8 | doi-access = free }}</ref> The latter is also formed from [[propionic acid]], which bacteria produce in the intestine.<ref name="Baumgartner_2014" /> Propionyl-CoA and [[bicarbonate]] are converted to Methylmalonyl-CoA by the enzyme [[Propionyl-CoA carboxylase|propionyl-CoA Carboxylase]].<ref name="Wongkittichote_2017" /> It then is converted into succinyl-CoA by [[methylmalonyl-CoA mutase]] (MUT). This reaction is a [[Reversible reaction|reversible]] [[isomerization]]. In this way, the compound enters the Citric Acid Cycle. The following diagram demonstrates the aforementioned reaction:<ref name="Lehninger4th">{{Lehninger4th||name-list-style=vanc}}</ref>

Propionyl CoA + Bicarbonate <big>→</big> Methylmalonyl CoA <big>→</big> Succinyl CoA

== Vitamin B₁₂ ==

[[Vitamin B12|Vitamin B₁₂]] plays an integral role in this reaction. Coenzyme B₁₂ ([[Adenosylcobalamin|adenosyl-cobalamin]]) is an [[Organometallic chemistry|organometallic]] form of [[Vitamin B12|Vitamin B₁₂]] and serves as the [[Cofactor (biochemistry)|cofactor]] of Methylmalonyl-CoA mutase, which is an essential [[enzyme]] in the human body.<ref name="Kräutler_2012">{{cite book | vauthors = Kräutler B |chapter=Biochemistry of B12-cofactors in human metabolism |date=2012 |title=Water Soluble Vitamins |series=Subcellular Biochemistry |volume=56 |pages=323–346 | veditors = Stanger O |place=Dordrecht |publisher=Springer Netherlands |doi=10.1007/978-94-007-2199-9_17 |pmid=22116707 |isbn=978-94-007-2198-2 }}</ref> The transformation of Methylmalonyl-CoA to Succinyl-CoA by this enzyme is a [[radical reaction]].<ref name="Kräutler_2012" />

== Related diseases ==

=== Methylmalonic Acidemia (MMA) ===

{{main|Methylmalonyl-CoA mutase deficiency}}

This disease occurs when methylmalonyl-CoA mutase is unable to isomerize sufficient amounts of methylmalonyl-CoA into succinyl-CoA.<ref name="Takahashi-Iñiguez_2012">{{cite journal | vauthors = Takahashi-Iñiguez T, García-Hernandez E, Arreguín-Espinosa R, Flores ME | title = Role of vitamin B12 on methylmalonyl-CoA mutase activity | journal = Journal of Zhejiang University. Science. B | volume = 13 | issue = 6 | pages = 423–437 | date = June 2012 | pmid = 22661206 | pmc = 3370288 | doi = 10.1631/jzus.B1100329 }}</ref> This causes a buildup of propionic and/or methylmalonic acid, which has effects on infants ranging from severe brain damage to death.<ref name="Baumgartner_2014" /> The disease is linked to Vitamin B₁₂, which is a cofactor for the enzyme methylmalonyl-CoA mutase.<ref name="Takahashi-Iñiguez_2012" /><ref name="Froese_2019">{{cite journal |vauthors=Froese DS, Fowler B, Baumgartner MR |date=July 2019 |title=Vitamin B₁₂ , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation |journal=Journal of Inherited Metabolic Disease |volume=42 |issue=4 |pages=673–685 |doi=10.1002/jimd.12009 |pmid=30693532 |doi-access=free}}</ref>

=== Combined malonic and methylmalonic aciduria (CMAMMA) ===

In the metabolic disease [[combined malonic and methylmalonic aciduria]] (CMAMMA), [[ACSF3|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.<ref>{{cite journal | vauthors = Gabriel MC, Rice SM, Sloan JL, Mossayebi MH, Venditti CP, Al-Kouatly HB | title = Considerations of expanded carrier screening: Lessons learned from combined malonic and methylmalonic aciduria | journal = Molecular Genetics & Genomic Medicine | volume = 9 | issue = 4 | pages = e1621 | date = April 2021 | pmid = 33625768 | pmc = 8123733 | doi = 10.1002/mgg3.1621 }}</ref><ref>{{cite journal | vauthors = Bowman CE, Wolfgang MJ | title = Role of the malonyl-CoA synthetase ACSF3 in mitochondrial metabolism | journal = Advances in Biological Regulation | volume = 71 | pages = 34–40 | date = January 2019 | pmid = 30201289 | pmc = 6347522 | doi = 10.1016/j.jbior.2018.09.002 }}</ref> The result is an accumulation of methylmalonic acid.

== References ==

{{Reflist}}

[[Category:Thioesters of coenzyme A]]