View source for 3-hydroxy-3-methylglutaryl-CoA lyase

{{enzyme
| Name = Hydroxymethylglutaryl-CoA lyase
| EC_number = 4.1.3.4
| IUBMB_EC_number = 4/1/3/4
| CAS_number= 9030-83-5
| GO_code = 0004419
| image = 2cw6.jpg
| width = 270
| caption = HMG-CoA lyase dimer, Human
}}
{{Infobox protein
| Name = 3-hydroxymethyl-3-methylglutaryl-Coenzyme A lyase (hydroxymethylglutaricaciduria)
| caption = 
| image = 
| width = 
| HGNCid = 5005
| Symbol = HMGCL
| AltSymbols = 
| EntrezGene = 3155
| OMIM = 246450
| RefSeq = NM_000191
| UniProt = P35914
| PDB = 
| ECnumber = 4.1.3.4
| Chromosome = 1
| Arm = p
| Band = 36.1
| LocusSupplementaryData = -p35
}}

'''3-hydroxy-3-methylglutaryl-CoA lyase''' (or '''[[HMG-CoA]] [[lyase]]''') is an [[enzyme]] that in human is encoded by the HMGCL [[gene]] located on [[chromosome 1]]. It is a key enzyme in [[ketogenesis]] ([[ketone body]] formation). It is a ketongenic 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. 

== Structure == 
The HMGCL gene encodes a 34.5-kDa protein that is localized to the [[mitochondrion]] and [[peroxisome]].<ref name="auto">{{cite journal |vauthors=Ashmarina LI, Robert MF, Elsliger MA, Mitchell GA |title=Characterization of the hydroxymethylglutaryl-CoA lyase precursor, a protein targeted to peroxisomes and mitochondria |journal=Biochem. J. |volume=315 ( Pt 1) |issue= |pages=71–5 |year=1996 |pmid=8670134 |pmc=1217198 |doi= |url=}}</ref> Multible [[isoform]]s of the proteins are known due to [[alternative splicing]]. The major isoform (isoform 1) is most highly expressed in the liver<ref name="auto"/> whereas isoform 2 is found in energy-demanding tissues including the [[brain]], [[heart]], and [[skeletal muscle]].<ref>{{cite journal |vauthors=Puisac B, Ramos M, Arnedo M, Menao S, Gil-Rodríguez MC, Teresa-Rodrigo ME, Pié A, de Karam JC, Wesselink JJ, Giménez I, Ramos FJ, Casals N, Gómez-Puertas P, Hegardt FG, Pié J |title=Characterization of splice variants of the genes encoding human mitochondrial HMG-CoA lyase and HMG-CoA synthase, the main enzymes of the ketogenesis pathway |journal=Mol. Biol. Rep. |volume=39 |issue=4 |pages=4777–85 |year=2012 |pmid=21952825 |doi=10.1007/s11033-011-1270-8 |url=}}</ref>

Structure of the HMGCL protein has been resolved by [[X-ray crystallography]] at 2.1-Å resolution, and reveals that the protein may function as a [[Protein dimer|dimer]]. [[Substrate (biochemistry)|Substrate]] access to the [[active site]] of the HMGCL enzyme involves substrate binding across a cavity located at the C-terminal end of a beta barrel structure.<ref>{{cite journal |vauthors=Fu Z, Runquist JA, Montgomery C, Miziorko HM, Kim JJ |title=Functional insights into human HMG-CoA lyase from structures of Acyl-CoA-containing ternary complexes |journal=J. Biol. Chem. |volume=285 |issue=34 |pages=26341–9 |year=2010 |pmid=20558737 |pmc=2924059 |doi=10.1074/jbc.M110.139931 |url=}}</ref> In addition, the lysine 48 residue which is mutated in patients with [[3-hydroxy-3-methylglutaryl-CoA lyase deficiency]] is also found to be necessary for substrate binding.<ref>{{cite journal |vauthors=Carrasco P, Menao S, López-Viñas E, Santpere G, Clotet J, Sierra AY, Gratacós E, Puisac B, Gómez-Puertas P, Hegardt FG, Pie J, Casals N |title=C-terminal end and aminoacid Lys48 in HMG-CoA lyase are involved in substrate binding and enzyme activity |journal=Mol. Genet. Metab. |volume=91 |issue=2 |pages=120–7 |year=2007 |pmid=17459752 |doi=10.1016/j.ymgme.2007.03.007 |url=}}</ref>

== Function ==
The HMGCL protein plays an essential role in breaking down dietary proteins and [[lipid|fats]] for energy.  It catalyzes the reaction:

(S)-3-hydroxy-3-methylglutaryl-CoA = acetyl-CoA + acetoacetate.

and requires a [[divalent]] metal ion as [[Cofactor (biochemistry)|co-factor]].<ref>{{cite journal |vauthors=Tuinstra RL, Miziorko HM |title=Investigation of conserved acidic residues in 3-hydroxy-3-methylglutaryl-CoA lyase: implications for human disease and for functional roles in a family of related proteins |journal=J. Biol. Chem. |volume=278 |issue=39 |pages=37092–8 |year=2003 |pmid=12874287 |doi=10.1074/jbc.M304472200 |url=}}</ref>

The enzyme is required for [[ketogenesis]] in the liver, and is also responsible for processing the [[amino acid]] [[leucine]] inside the [[mitochondrion]]

Deficiency 
HMG-CoA lyase deficiency causes hypoketotic hypoglycemia similar to that is caused by HMGCS2 mutations but also leads to organic acid accumulation and metabolic acidosis due to altered leucine metabolism. This disorder can be mistaken for Reye syndrome because of the symptoms of vomiting, lethargy, and convulsions.    

[[Image:Ketogenesis.svg|350px|thumb|center|[[Ketogenesis]]]]

==Clinical significance==
[[Mutation]]s in the ''HMGCL'' [[gene]] cause [[3-hydroxy-3-methylglutaryl-CoA lyase deficiency]] (HMGCLD), a rare [[autosomal recessive]] [[inborn error of metabolism]] characterized by disruption of [[ketogenesis]] and [[L-leucine]] [[catabolism]]. To-date more than 30 different mutations including [[missense mutation]]s of different residues have been associated with patients with HMGCLD in diverse families and ethnicities.<ref>{{cite journal |vauthors=Menao S, López-Viñas E, Mir C, Puisac B, Gratacós E, Arnedo M, Carrasco P, Moreno S, Ramos M, Gil MC, Pié A, Ribes A, Pérez-Cerda C, Ugarte M, Clayton PT, Korman SH, Serra D, Asins G, Ramos FJ, Gómez-Puertas P, Hegardt FG, Casals N, Pié J |title=Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria |journal=Human Mutation |volume=30 |issue=3 |pages=E520–9 |year=2009 |pmid=19177531 |doi=10.1002/humu.20966 }}</ref> HMGCLD typically presents in the first year of the patient's life after a fasting period. Clinical acute symptoms include vomiting, [[seizure]]s, metabolic [[acidosis]], hypoketotic [[hypoglycemia]], and lethargy.<ref>{{OMIM|246450|3-hydroxy-3-methylglutaryl-coa lyase deficiency; HMGCLD}}</ref>

== Interactions == 
HMGCL interacts with itself to form [[homodimer]]s and [[homotetramer]]s. It is also shown in [[yeast two-hybrid]] experiments to interact with [[DNAJA1]].

==References==
{{reflist|30em}}

==External links==
* {{MeshName|3-hydroxy-3-methylglutaryl-coenzyme+A+lyase}}

{{Mevalonate pathway, bile acids, steroids}}
{{Amino acid metabolism enzymes}}
{{Carbon-carbon lyases}}
{{Enzymes}}
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[[Category:EC 4.1.3]]


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