Krebs Fumarase

Defects of the Krebs cycle. Fumarase deficiency was reported in children with mitochondrial encephalomyop-athy. Usually, there is developmental delay since early infancy, microcephaly, hypotonia and cerebral atrophy, with death in infancy or early childhood. The laboratory hallmark of the disease is the excretion of large amounts of fumaric acid and, to a lesser extent, succinic acid in the urine. The enzyme defect has been found in muscle, liver and cultured skin fibroblasts [16]. 

C-IO) Fumarase deficiency. There is a deficit in the transformation of fumarate to malate. The infant has developmental retardation, with abnormal neuromuscular function, lactic acidemia, and fumarate aciduria. The lactic acidosis may result from a backup of Krebs cycle function, all the way to lactate. Lactic acidosis may also be present in rare disorders of cytochrome oxidase activity. Diagnostically, there is a deficit in fumarase activity in assay of liver and skeletal muscle mitochondria. 

The uiea cycle may be considered to be a mitochondrial pathway, as carbamyl phosphate synthase and ornithine transcarbamylase are mitochondrial enzymes however, the enzymes catalyzing subsequent steps of the pathway arc cytosolic-The steps leading to conversion of citrulline to ornithine occur in the cytosol. Hence, the pathway is shared by the mitochondrial and cytosolic compartments. The fumarate produced by the urea cycle is converted to malate by a cytoplasmic form of fumarase. Mittxihondrial fumarase is part of the Krebs cycle. Cytoplasmic malate can enter the mitochondrion by means of a transport system, such as the malate/phosphate exchanger or the ma ate/a-ketoglutaratc exchanger. These transport systems are membrane-bound proteins. 

Fumarase. A powerful fumarase is found in the cells of P. shermanii (Krebs and Egglestone, 1941). The enzyme catalyzes interconversions between fumarate and malate ... 

Deficiency of fumarase causes marked elevations of fumaric acid and often other Krebs cycle intermediates in the urinary organic acids profile. The diagnosis is confirmed by measurement of fumarase activity in cultured skin fibroblasts, leukocytes or affected organs. For defining the carrier status of family members, fumarase activity measurement in blood mononuclear cells appears to be a good, easy screening tool [7-9]. Mutation analysis can confirm the results of enzyme studies [11]. 

The fumaric acid passes into the tricarboxylic add cycle or in the presence of fumarase it is transformed to malic add which also enters the Krebs cycle. 

Fig. 2.7. Tricarboxylic acid or Krebs cycle. 1 = citrate synthase 2-3 = aconitase 4 = isocitrate dehydrogenase 5 = complex a-ketoglutarate dehydrogenase 6 = snccinyl-CoA synthetase, 7 = succinate dehydrogenase 8 = fumarase 9 = malate dehydrogenase GTP = guanosine triphosphate GDP = guanosine diphosphate...

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