View source for Methylmalonyl-CoA mutase deficiency

{{Infobox medical condition |
  Name           = Methylmalonyl-CoA mutase deficiency |
  ICD10          = |
  ICD9           = |
  ICDO           = |
  Image          = |
  Caption        = |
  OMIM           = 251000 |
  MedlinePlus    = |
  eMedicineSubj  = |
  eMedicineTopic = |
  DiseasesDB     = 29509}}
{{Infobox protein
| name = [[Methylmalonyl-CoA mutase]]
| image = Protein_MUT_PDB_2XIJ.png
| width = 
| caption = Rendering based on [[Protein Data Bank|PDB]] {{PDB2|2XIJ}}.
| Symbol = [[Methylmalonyl-CoA mutase|MUT]]
| AltSymbols = MCM
| EntrezGene = 4594
| HGNCid = 4594
| OMIM = 609058
| RefSeq = NP_000246
| UniProt = P22033
| ECnumber = 5.4.99.2
| Chromosome = 6
| Arm = p
| Band = 21
| LocusSupplementaryData = 
}}
{{enzyme
| Name = methylmalonyl-CoA mutase
| EC_number = 5.4.99.2
| CAS_number = 9023-90-9
| IUBMB_EC_number = 5/4/99/2
| GO_code = 0004494
| image =
| width =
| caption =
}}
[[Methylmalonyl-CoA mutase]] is a mitochondrial homodimer apoenzyme (EC. 5. 4.99.2) 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'''<ref>{{OMIM|251000}}</ref> is caused by genetic defect in the MUT <ref>{{cite web|title=Genebase on MUT|url=http://www.genecards.org/cgi-bin/carddisp.pl?gene=MUT}}</ref> gene responsible for encoding the enzyme. Deficiency in this enzyme accounts for 60% of the cases of [[methylmalonic acidemia]].<ref>{{OMIM|251100}}</ref>

==Symptoms==

People with methylmalonyl CoA mutase deficiency exhibit many symptoms similar to other diseases involving [[inborn errors of metabolism]]. Sometimes the symptoms appear shortly after birth, but other times the onset of symptoms is later.

Newborn babies experience with vomiting, [[acidosis]], [[hyperammonemia]], [[hepatomegaly]] (enlarged livers), [[hyperglycinemia]] (high [[glycine]] levels), and [[hypoglycemia]] (low blood sugar). Later, cases of [[thrombocytopenia]] and [[neutropenia]] can occur.

In some cases intellectual and developmental disabilities, such as [[autism]], were noted with increased frequency in populations with methylmalonyl-CoA mutase deficiency.<ref name="pmid7985563">{{cite journal |vauthors=Brismar J, Ozand PT | title = CT and MR of the brain in disorders of the propionate and methylmalonate metabolism | journal = AJNR Am J Neuroradiol | volume = 15 | issue = 8 | pages = 1459–73 |date=September 1994 | pmid = 7985563 | doi = }}</ref>

==Causes==

While methylmalonic acidemia has a variety of causes, both genetic and dietary, methylmalonyl CoA mutase deficiency is an autosomal recessive genetic disorder. Patients suffering from the deficiency either have a complete gene lesion, designated as mut0 or a partial mutation in the form of a frameshift designated as mut-. This frameshift affects the folding of the enzyme rendering its binding domain less effective.<ref name="pmid1979918">{{cite journal |vauthors=Kennedy DG, Cannavan A, Molloy A, O'Harte F, Taylor SM, Kennedy S, Blanchflower WJ | title = Methylmalonyl-CoA mutase (EC 5.4.99.2) and methionine synthetase (EC 2.1.1.13) in the tissues of cobalt-vitamin B12 deficient sheep | journal = Br. J. Nutr. | volume = 64 | issue = 3 | pages = 721–32 |date=November 1990 | pmid = 1979918 | doi = 10.1079/bjn19900074}}</ref> Patients with a complete deletion suffer an inactivation of methylmalonyl CoA mutase and exhibit the most severe symptoms of the deficiency, while patients with a partial mutations have a wide range of symptoms. Over 49 different mutations<ref name="pmid11528502">{{cite journal |vauthors=Acquaviva C, Benoist JF, Callebaut I, Guffon N, Ogier de Baulny H, Touati G, Aydin A, Porquet D, Elion J | title = N219Y, a new frequent mutation among mut(degree) forms of methylmalonic acidemia in Caucasian patients | journal = Eur. J. Hum. Genet. | volume = 9 | issue = 8 | pages = 577–82 |date=August 2001 | pmid = 11528502 | doi = 10.1038/sj.ejhg.5200675 }}</ref> have been discovered for the MUT gene, yet only two appear in any discernible frequency.

==Enzymatic activity==

Methylmalonyl-CoA mutase catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, and uses a B12 derived prosthetic group, adenosylcobalamin, in order to accomplish this transfer. The enzyme is a homodimer, located in the mitochondrial matrix. The enzyme is 750 amino acids long, with the a metal ligand binding region to bind to the Cobalt region of adenosylcobalamin.<ref name="Ledley_ Rosenblatt_1997"/>

The enzyme works by cleaving the adenosylcobalamin C-Co(III) bond, giving the carbon and cobalt (III) atoms each an electron. The cobalt then fluctuates between its two oxidation states: Co(II) and Co(III). In this way the adenosylcobalamin works as a reversible free radical generator. The cobalt therefore donates an electron back to the methylmalonyl-CoA backbone in order to transfer the coenzyme A group.<ref name="Ledley_ Rosenblatt_1997">{{cite journal |vauthors=Ledley FD, Rosenblatt DS | title = Mutations in mut methylmalonic acidemia: clinical and enzymatic correlations | journal = Hum. Mutat. | volume = 9 | issue = 1 | pages = 1–6 | year = 1997 | pmid = 8990001 | doi = 10.1002/(SICI)1098-1004(1997)9:1<1::AID-HUMU1>3.0.CO;2-E }}</ref>

[[Image:MUT.png|500px|MUT's reaction mechanism]]

==Metabolic activity==

Methylmalonyl-CoA mutase is essential to the degradation pathways of many molecules including amino acids, and [[odd-chain fatty acid]]s. Methylmalonyl-CoA mutase links the propionyl-CoA degradation byproduct of these macromolecules to the tricarboxylic acid cycle.<ref name="Ledley_ Rosenblatt_1997"/><!-- Deleted image removed: [[File:Methylmalonyl pathways following amino acid degradation.gif|thumb|right|300px|Metabolic pathway of methylmalonyl-CoA mutase following amino acid degradation.]] --><!-- Commented out because image was deleted: [[File:Methylmalonyl pathway following methionine and homocysteine degradation.gif|thumb|right|300px|Pathway of methylmalonyl-CoA mutase following methionine degradation]] -->

For amino acid metabolism, methylmalonyl-CoA mutase works in the degradation pathways of [[isoleucine]], [[threonine]], [[valine]], and [[methionine]]. These amino acids are degraded into [[propanoyl-CoA]] which is then further degraded into  (S)-methylmalonyl-CoA. This substrate must be further metabolized by a very similar enzyme, methylmalonyl-CoA epimerase, which converts the (S) form of methylmalonyl-CoA into the (R) form. This is finally transformed using methylmalonyl-CoA mutase. L-methionine is also metabolized through a longer superpathway (see Figure 2). After transformation to L-homocystein, it is combined with L-serine to make L-cystathione, which is hydrolyzed by cystathione gamma lyase to create 2-oxobutanoate. This substrate is transformed to [[propionyl-CoA]] and undergoes the same metabolism previously described for propionyl-CoA.<ref name = "Berg_2002">{{cite book|year=2002|vauthors=Berg JM, Tymoczko JL, Stryer L |chapter=Section 22.3: Certain Fatty Acids Require Additional Steps for Degradation|edition=5th|title=Biochemistry}}</ref>

The cholesterol superpathway follows the degradation of cholesterol down to various substrates, however only a couple of these biotransformed molecules see propionyl-CoA as a byproduct. The conversion of 3,24-dioxocholest-4-en-26-oyl-CoA to 2-oxochol-4-en-24-oyl-CoA sees the release of a propionyl-CoA molecule. Additionally, the conversion of 3-oxo-23,24-bisnorchol-4-en-17-ol-22-oyl-CoA to androst-4-ene-3,17-dione release of a propionyl-CoA molecule. Finally, the degradation of (S)-4-hydroxy-2-oxohexanoate to pyruvate and propanal, in turn releases a propionyl-CoA substrate after the propanal is converted. All these propionyl-CoA substrates are converted to succinyl-CoA following the methylmalonyl pathway For amino acid metabolism, methylmalonyl-CoA mutase works in the degradation pathways of [[isoleucine]], [[threonine]], [[valine]], and [[methionine]]. These amino acids are degraded into [[propanoyl-CoA]] which is then further degraded into  (S)-methylmalonyl-CoA. This substrate must be further metabolized by a very similar enzyme, methylmalonyl-CoA epimerase, which converts the (S) form of methylmalonyl-CoA into the (R) form. This is finally transformed using methylmalonyl-CoA mutase. L-methionine is also metabolized through a longer superpathway (see Figure 2). After transformation to L-homocystein, it is combined with L-serine to make L-cystathione, which is hydrolyzed by cystathione gamma lyase to create 2-oxobutanoate. This substrate is transformed to propanoyl-CoA and undergoes the same metabolism previously described for propanoyl-CoA.<ref name = "Berg_2002"/>

Odd chain fatty acids are also metabolized through the methylmalonyl pathway. The degradation of odd chain fatty acids releases Acetyl-CoA and propionyl-CoA. Propionyl-CoA is then converted to succinyl-CoA, and both succinyl-CoA and propionyl-CoA are interjected into the tricarboxylic acid cycle for continued production of reductant.<ref name="pmid2567699">{{cite journal |vauthors=Jansen R, Kalousek F, Fenton WA, Rosenberg LE, Ledley FD | title = Cloning of full-length methylmalonyl-CoA mutase from a cDNA library using the polymerase chain reaction | journal = Genomics | volume = 4 | issue = 2 | pages = 198–205 |date=February 1989 | pmid = 2567699 | doi = 10.1016/0888-7543(89)90300-5}}</ref>

==Metabolic pathology==

[[File:Urea cycle 2.png|400px|right|Urea cycle colored.]]

The final product of methylmalonyl-CoA mutase activity is succinyl-CoA which is a tricarboxylic acid cycle substrate. A side effect of excess methylmalonyl-CoA is an interruption of the enzymes responsible for other transformations earlier in the metabolism of propionyl-CoA, leading to propanoic acidemia as well. This, along with an excess of methylmalonyl-CoA leads to the depletion of ATP through oxidative stress and coenzyme A. This disrupts the biosynthesis of myelin, urea, and glucose.<ref name = "Yudkoff_1999">{{cite book|vauthors=Yudkoff M, Siegel GJ, Agranoff BW, Albers RW |chapter=Organic Acid Metabolism|edition=6th|year=1999|title=Basic Neurochemistry: Molecular, Cellular, and Medical Aspects}}</ref> Specifically, excess methylmalonyl-CoA places oxidative stress on the mitochondrial enzymes involved in the urea cycle (such as ammonia-dependent-carbamoyl-phosphate synthase or CPS1), and inhibits its mechanism of action.<ref name="pmid4056969">{{cite journal |vauthors=Hudak ML, Jones MD, Brusilow SW | title = Differentiation of transient hyperammonemia of the newborn and urea cycle enzyme defects by clinical presentation | journal = J. Pediatr. | volume = 107 | issue = 5 | pages = 712–9 |date=November 1985 | pmid = 4056969 | doi = 10.1016/s0022-3476(85)80398-x}}</ref> The combination of inhibited urea synthesis and poor protein metabolism, as well as a weakly replenished tricarboxylic acid cycle contribute to the symptoms of methylmalonic acidemia.

==Diagnosis and treatment==

Several tests can be done to discover the dysfunction of methylmalonyl-CoA mutase. Ammonia test, blood count, CT scan, MRI scan, electrolyte levels, genetic testing, methylmalonic acid blood test, and blood plasma amino acid tests all can be conducted to determine deficiency.

There is no treatment for complete lesion of the mut0 gene, though several treatments can help those with slight genetic dysfunction. Liver and kidney transplants, and a [[low-protein diet]] all help regulate the effects of the diseases.<ref>{{cite web|title=Medline infomatics|url=http://www.nlm.nih.gov/medlineplus/ency/article/001162.html}}{{dead link|date=December 2013}}</ref>

== Prognosis ==
Infant mortality is high for patients diagnosed with early onset; mortality can occur within less than 2 months, while children diagnosed with late-onset syndrome seem to have higher rates of survival.<ref name="pmid16750411">{{cite journal |vauthors=Kaplan P, Ficicioglu C, Mazur AT, Palmieri MJ, Berry GT | title = Liver transplantation is not curative for methylmalonic acidopathy caused by methylmalonyl-CoA mutase deficiency | journal = Mol. Genet. Metab. | volume = 88 | issue = 4 | pages = 322–6 |date=August 2006 | pmid = 16750411 | doi = 10.1016/j.ymgme.2006.04.003 }}</ref> Patients suffering from a complete lesion of mut0 have not only the poorest outcome of those suffering from methylaonyl-CoA mutase deficiency, but also of all individuals suffering from any form of methylmalonic acidemia.

==See also==
* [[Methylmalonyl-CoA mutase]]

==References==
{{reflist|2}}
==External links==
* {{NLM|methylmalonicacidemia}}

{{Amino acid metabolic pathology}}

{{DEFAULTSORT:Methylmalonyl-Coa Mutase Deficiency}}
[[Category:Amino acid metabolism disorders]]