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INTRODUCCIÓN: La Unidad de Bioinformática del Centro de
Biología Molecular "Severo Ochoa".
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PRÁCTICA. PREDICCIÓN, BASADA EN ESTRUCTURA, DE LA ACTIVIDAD
DE UNA ENZIMA CON UNA MUTACIÓN PUNTUAL:
SOFTWARE:
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Enzime: HMGL_HUMAN.
3-hydroxy-3-methylglutaryl-CoA ===> acetyl-CoA + acetoacetate.
3-Hydroxy-3-methylglutaric aciduria (MIM246450)
is a rare autosomal recessive metabolic disorder appearing in the 1st year
of life. Acute episodes include vomiting, lethargy, hypotonia, and apnea,
sometimes evolving to coma. Laboratory tests reveal metabolic acidosis
with severe hypoketotic hypoglycemia on fasting or during acute illness,
hyperammonemia, and abnormal liver function tests. The disease is fatal
in about 20% of cases although the symptoms are milder after childhood.
The origin of the disease is a mutation in the gene coding for 3-hydroxy-3-methylglutaryl-coenzyme
A (HMG-CoA)1 lyase, which cleaves HMG-CoA to form acetyl-CoA and acetoacetate.
This is the final step in the ketogenic pathway and leucine catabolism.
The gene was assigned to the distal short arm of human chromosome 1p36.1
It contains 9 exons and is transcribed in an mRNA of 1.7 kb. The presence
of the protein inside mitochondria and peroxisomes has been reported. The
active site of HL has been shown to include the residues Cys266 and His233.
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Modeled structure: [HMGL_no_substrate.pdb]
[HMGL_substrate.pdb]
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MUTANT 1: Val70 --> Arg.
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Modeled structure of mutant 1: [V70R_no_substrate.pdb]
[V70R_substrate.pdb]
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Additional proposed mutants: Ser201 --> Tyr; Asp204 -->
Arg; Ser75 --> Arg.
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