Enzymes, metabolic pathways, flux control analysis, and the enzymology of specific groups of inherited metabolic diseases

Abstract

Enzyme functions in a particular metabolic pathway are best described by K m and V max values. The central parameter in metabolic flux analysis is that of control strength, alternatively called flux control coefficient. It is described by the flux control coefficient which is set between 0 and 1. A flux control coefficient of 1 means that the particular enzyme has full control of flux through the pathway, whereas a flux control coefficient of 0 implies that the particular enzyme exerts virtually no control of flux. In any patient with a Zellweger spectrum-like phenotype in which very long-chain fatty acids have been found abnormal, a full enzymatic study in fibroblasts is warranted in order to resolve whether the patient has a defect in the biogenesis of peroxisomes or is affected by a single peroxisomal enzyme deficiency. The introduction of tandem mass spectrometry has revolutionized the diagnosis of fatty acid oxidation (FAO) disorders. Acylcarnitine analysis is the first-line test in patients suspected to suffer from an FAO disorder. If abnormal, enzyme studies should be performed to resolve the underlying enzymatic defect. Biochemical diagnostics of mitochondrial disorders usually involves a broad screening of mitochondrial enzyme activities and analysis of fluxes through the citric acid cycle and oxi-dative phosphorylation system. The analysis of fluxes can only be performed in freshly obtained tissue samples (usually muscle). Determination of the activity of lysosomal enzymes in leukocytes, plasma or dried blood spots, or in fibroblasts is the core in the laboratory diagnosis of lysosomal storage disorders. © 2010 Springer-Verlag Berlin Heidelberg.