0 mutations Thiamine, deficiency

TAs one might predict, mutations in the genes for the subunits of the PDH complex, or a dietaiy thiamine deficiency, can have severe consequences. Thiamine-deficient animals are unable to oxidize pyruvate normally. This is of particular importance to the brain, which usually obtains all its energy from the aerobic oxidation of glucose in a pathway that necessarily includes the oxidation of pyruvate. Beriberi, a disease that results from thiamine deficiency, is characterized by loss of neural function. This disease occurs primarily in populations that rely on a diet consisting mainly of white (polished) rice, which lacks the hulls in which most of the thiamine of rice is found. People who habitually consume large amounts of alcohol can also develop thiamine deficiency, because much of their dietaiy intake consists of the vitamin-free empty calories of distilled spirits. An elevated level of pyruvate in the blood is often an indicator of defects in pyruvate oxidation due to one of these causes. ... 

Wernicke Korsakoff syndrome (WKS) is the neurological disorder most clearly linked to thiamine deficiency in humans. WK develops in a subset of chronic alcoholics, who are vitamin deficient because so many calories are consumed as alcohol instead of normal diet, and a diet rich in carbohydrates increases the metabolic demand for thiamine. Thiamine dependent enzymes were diminished in the brains of patients who died with WKS, but not in alcoholic controls (Butterworth et al., 1993). Transketolase in fibroblasts from those patients who develop WKS syndrome binds TPP more avidly than the control lines. The Km was nearly ten times higher in patients with WKS. Thus, these patients have an abnormahty of transketolase that would be clinically unimportant if the diet was adequate (Blass and Gibson, 1977, 1979). The latter demonstrate a predisposing biochemical mutation to a neurological diseases that is only revealed by inadequate diet. 

Clinical manifestations of thiamine deficiency develop in only a small fraction of alcoholics and other chronically malnourished people. Do some patients have an inborn predisposition to developing neurologic disease with thiamine deficiency Four alcoholics with the disease were shown to have a cellular defect in the enzyme transketolase (Blass and Gibson, 1977). The defective enzyme bound thiamine pyrophosphate with only 5-10% of the normal avidity. Presumably, this represents a genetically determined structural mutation in transketolase. When diet is adequate, the genetic abnormality would be clinically silent, but with the stress of marginal thiamine intake, affected individuals would more readily develop disease. 

Thiamin-related diseases are the result of either insulficient thiamin intake (thiamin deficiency), poisoning by antithiamins, or of mutations in thiamin transporters or thiamin diphosphate-dependent enzymes. 

Most early clinical descriptions of apparent thiamine-responsive PDC deficiency were not characterized biochemically to ascertain true thiamine dependence. In subsequent reports, immunochemical analyses have demonstrated varied patterns of a- and P-subunit expression, and in vitro studies of cultured cells have sometimes found altered El enzyme kinetics (high Km, low Vmax) for TPP. When molecular genetic analyses have been undertaken, different mutations have been identified within the conserved TPP-binding motif that are considered to lead to diminished binding affinity for TPP or to decreased stability of the oc2P2 tetramer. 

Naito E, Ito M, Yokota I, Saijo T, Matsuda J, Ogawa Y et al. Thiamine-responsive pyruvate dehydrogenase deficiency in two patients caused by a point mutation (F205L and L216F) within the thiamine pyrophosphate binding region. Biochim Biophys Acta 2002 1588 79-84. 

The pathway as presented in Table I shows that it is linear for the first 10 steps with no branch points before the pivotal IMP is formed. However, a branch point does exist for the synthesis of the pyrimidine moiety (Bi-pyrimidine) of thiamine. Convincing evidence has been obtained to indicate that AIR also serves as a precursor to Bi-pyrimi-dine [27]. This explains the concomitant growth requirement for thiamine for most of the mutants blocked in any one of the first five enzymes [27-29]. A complication in regulatory control is thus introduced in that any attempt to control purine biosynthesis at the first five steps would have dire consequences on the formation of thiamine. This has indeed been found in the often-reported cases where inhibition of growth by adenine and its derivatives can be reversed by thiamine or its pyrimidine moiety [29-31]. The situation is more complicated in a special class of adenine-sensitive mutants where the sensitivity appears to be related to disturbances in folic acid metabolism [32]. Mutations in the AICAR formyltransferase complex (steps 9 and 10) also create a pleiotropic thiamine requirement which is not due to a deficiency in the synthesis of thiamine but rather to an unexplained phenotypic... 

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