Molecular genetics of HMG-CoA lyase deficiency

Pié, Juan; López-Viñas, Eduardo; Puisac, Beatriz; Menao, Sebastián; Pié, Ángeles; Casale, César H.; Ramos, Feliciano J.; Hegardt, Fausto G.; Gómez‐Puertas, Paulino; Casals, Núria

doi:10.1016/j.ymgme.2007.06.020

Cited by 69 publications

(37 citation statements)

References 80 publications

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“…Outcome of this inherited disease can be lethal if uncontrolled (5). An extensive compilation of missense human HMGCL mutations has been included in a recent review article (6).…”

Section: -Hydroxy-3-methylglutaryl-coa Lyase-like Protein (Hmg-cll1)mentioning

confidence: 99%

Identification and Characterization of an Extramitochondrial Human 3-Hydroxy-3-methylglutaryl-CoA Lyase

Montgomery

Pei

Watkins

et al. 2012

Journal of Biological Chemistry

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Background: Ketone bodies have been implicated not only in energy metabolism, but also in lipogenesis. Results: Discovery and characterization of human extramitochondrial HMG-CoA lyase-like protein (HMGCLL1) has been accomplished. Conclusion: Catalytically active HMGCLL1 is myristoylated and vesicle associated. Significance: Extramitochondrial HMG-CoA lyase may be crucial to lipid biosynthesis or to energy metabolism in certain tissues and cancer cells.

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“…Outcome of this inherited disease can be lethal if uncontrolled (5). An extensive compilation of missense human HMGCL mutations has been included in a recent review article (6).…”

Section: -Hydroxy-3-methylglutaryl-coa Lyase-like Protein (Hmg-cll1)mentioning

confidence: 99%

Identification and Characterization of an Extramitochondrial Human 3-Hydroxy-3-methylglutaryl-CoA Lyase

Montgomery

Pei

Watkins

et al. 2012

Journal of Biological Chemistry

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“…A variety of human mutations, including many point mutations in protein-coding exons of the gene, have been documented (6). A computational modeling approach was used to explain the molecular basis for some mutations linked to inherited disease (7).…”

mentioning

confidence: 99%

Functional Insights into Human HMG-CoA Lyase from Structures of Acyl-CoA-containing Ternary Complexes

Runquist

Montgomery

et al. 2010

Journal of Biological Chemistry

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HMG-CoA lyase (HMGCL 4 ; EC 4.1.3.4) catalyzes a cationdependent cleavage of substrate into acetyl-CoA and acetoacetate (Scheme 1) (1). This reaction is a key step in ketogenesis, the products of which support anaplerotic metabolism in bacteria (2) and energy production in nonhepatic animal tissues (3). Ketogenesis is particularly important to human metabolism during the prenatal period and during fasting or starvation. In accordance with these physiological roles, it is not surprising that gene knock-out in mice results in embryonic lethality (4). The physiological importance of the enzyme in humans is underscored by the observation that mutations that diminish HMGCL activity correlate with inherited metabolic disease that can be lethal if uncontrolled (5).A variety of human mutations, including many point mutations in protein-coding exons of the gene, have been documented (6). A computational modeling approach was used to explain the molecular basis for some mutations linked to inherited disease (7). This led to the prediction that HMGCL adopts a ␤/␣-barrel fold and a proposal that the acyl-S-pantetheine moiety of the bound substrate passes through the barrel lumen. Initial structural work on human HMGCL liganded to cation and hydroxyglutarate (8) demonstrated that the folding prediction was reasonable but that the substrate binding proposal was unlikely to be correct. The positions of bound cation and hydroxyglutarate (from hydrolyzed hydroxyglutaryl-CoA) indicated the catalytic site to be positioned at the C-terminal end of the barrel, but the absence of a full acyl-CoA molecule in the experimentally determined structure limited detailed insight into the substrate-binding site.To more fully address questions regarding the conformation of bound substrate, activator cation liganding, details concerning reaction chemistry and specificity, as well as the molecular basis for certain inherited HMGCL deficiencies, new structural information on enzyme bound to an intact acyl-CoA molecule is required. To remedy this need, complexes of the WT enzyme with the competitive inhibitor 3-hydroxyglutaryl-CoA and also of catalytically deficient R41M enzyme with the authentic substrate HMG-CoA have been supplemented with the activator cation Mg 2ϩ , and crystallization of the desired ternary complexes has been accomplished. Diffraction quality crystals have been produced, supporting three-dimensional structural determinations for ternary complexes of enzyme, cation, and either the acyl-CoA substrate or inhibitory analog. These findings are

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“…Clinically, patients show different acute episodes including vomiting, hypotonia, lethargy, diarrhea, cyanosis, dehydration, hypothermia, hepatomegalia and macrocephalia (Gibson et al, 1988a, b). Some patients may present non-common signs as hepatomegalia, macrocephalia, dilated cardiomyopathy with arrhythmia, and delayed development (Pié et al, 2007). About 20% of HMG-CoA lyase deficiency cases progress and cause permanent neurological damage and death (Gibson et al, 1988a).…”

Section: Discussionmentioning

confidence: 99%

“…Patients who are presented in hospital with acute episodes are given glucose and bicarbonate to control hypoglycemia and acidosis, respectively. The severity of illness decreases with age, and adults generally are free of symptoms (Pié et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Recurrent mutation in the HMGCL gene in a family segregating HMG-CoA lyase deficiency

Alharby¹,

Malibari²,

Al-Otaibi³

et al. 2016

Int. J. Genet. Mol. Biol.

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Arg41Gln). This is the most frequent mutation found in the HMGCL gene in Saudi population and might have occurred due to a founder effect. Multiple in silico software predicted this mutation as disease-causing. Moreover, to determine the protein stability upon change in amino acid various tools including SDM, I-Mutant, mCSM and DUET were used and found that the mutation, identified in this family, is protein destabilizing. An extensive literature review was performed and all mutations reported to date in the HMGCL gene were identified and listed.

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Molecular genetics of HMG-CoA lyase deficiency

Cited by 69 publications

References 80 publications

Identification and Characterization of an Extramitochondrial Human 3-Hydroxy-3-methylglutaryl-CoA Lyase

Identification and Characterization of an Extramitochondrial Human 3-Hydroxy-3-methylglutaryl-CoA Lyase

Functional Insights into Human HMG-CoA Lyase from Structures of Acyl-CoA-containing Ternary Complexes

Recurrent mutation in the HMGCL gene in a family segregating HMG-CoA lyase deficiency

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