Differential HMG-CoA lyase expression in human tissues provides clues about 3-hydroxy-3-methylglutaric aciduria.
3-Hydroxy-3-methylglutaric aciduria is a rare human autosomal recessive disorder caused by deficiency of 3-hydroxy-3-methylglutaryl CoA lyase (HL). This mitochondrial enzyme catalyzes the common final step of leucine degradation and ketogenesis. Acute symptoms include vomiting, seizures and lethargy, accompanied by metabolic acidosis and hypoketotic hypoglycaemia. Such organs as the liver, brain, pancreas, and heart can also be involved. However, the pathophysiology of this disease is only partially understood. We measured mRNA levels, protein expression and enzyme activity of human HMG-CoA lyase from liver, kidney, pancreas, testis, heart, skeletal muscle, and brain. Surprisingly, the pancreas is, after the liver, the tissue with most HL activity. However, in heart and adult brain, HL activity was not detected in the mitochondrial fraction. These findings contribute to our understanding of the enzyme function and the consequences of its deficiency and suggest the need for assessment of pancreatic damage in these patients.
Puisac
Beatriz
B
Laboratory of Clinical Genetics and Functional Genomics, Department of Pharmacology and Physiology, School of Medicine, University of Zaragoza, C/ Domingo Miral s/n, 50009, Zaragoza, Spain.
Arnedo
María
M
Casale
Cesar H
CH
Ribate
María Pilar
MP
Castiella
Tomás
T
Ramos
Feliciano J
FJ
Ribes
Antonia
A
Pérez-Cerdá
Celia
C
Casals
Nuria
N
Hegardt
Fausto G
FG
Pié
Juan
J
D000143:Acids / Q000652:urine*; D000368:Aged; D001921:Brain / Q000201:enzymology; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008297:Male; D015093:Meglutol / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology; D009928:Organ Specificity; D007652:Oxo-Acid-Lyases / Q000235:genetics* / Q000378:metabolism*; D010179:Pancreas / Q000201:enzymology; D017354:Point Mutation; D012333:RNA, Messenger / Q000378:metabolism; D013737:Testis / Q000201:enzymology
D000143:Acids; D012333:RNA, Messenger; D015093:Meglutol; D007652:Oxo-Acid-Lyases; C021410:3-hydroxy-3-methylglutaryl-coenzyme A lyase