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Dihydrolipoamide dehydrogenase (E3) (dihydrolipoamide:NAD+ oxidoreductase; EC 1.8.1.4) is an integral compo­ nent in pyruvate,1 a-ketoglutarate,1 branched-chain a-keto acid dehydrogenase complexes,1 and the glycine cleavage system.2 E3 facilitates reoxidation of the dihydrolipoyl group of the acyltransferase components of a-keto acid dehydrogenase complexes and the hydrogen-carrier pro­ tein of the glycine cleavage system. E3 is a homodimeric flavoenzyme containing a single FAD at each subunit (Figure 1). E3 is a member of the pyridine nucleotide-disulfide oxidoreductase family along with glutathione reductase, thioredoxin reductase, mercuric reductase, and trypanothione reductase.3 Their structures are similar, having four structural domains (FAD, NAD, central and interface domains). Their homodimeric structures contain an active disulfide center and a FAD domain in each subunit. Their catalytic mechanisms are also similar, catalyzing electron transfer between the pyridine nucleotides (NAD+ or NADPH) and their specific substrates through FAD and the active disul­ fide center. Patients with an E3 deficiency present with a variety of clinical symptoms, ranging from Leigh syndrome, serious neurological disease, to exertional fatigue.4 Because E3 is a common essential component in three a-keto acid dehy­ drogenase complexes, a reduction of E3 activity leads to a decrease in the activities of all three complexes. Patients show increased urinary excretion of keto acids, and elevated blood levels of lactate, pyruvate and branched chain amino acids. The central nervous system, such as the brain is most commonly affected by these genetic defects because the system normally uses glucose as a principle energy source. One mutation found in patients with low E3 activity is the Arg-447 to Gly mutation.5 Patients with this mutation suf­ fer from neurological deterioration and generally die within 3 years. Figure 2 presents the sequence alignment of the sequence around the Arg-447 region of human E3 with the corre­ sponding regions of E3s from a range of sources, such as pigs, yeast, Escherichia coli, and Pseudomonasfluorescens. Arg-447 is conserved in eukaryotic E3s, suggesting that Arg-447 might be important for the function and structure of these E3s, including human E3. Arg-447 is located imme­ diately behind short a-helix structure 12 (Figure 3), which is composed of 5 amino acids and a component of the interface domain. This study examined the effects of the naturally occurring Arg-447 to Gly mutation on the human E3 structure and function, leading to neurological dete­ rioration.

journal of the korean chemical society

Characterization of a Naturally Occurring Mutation (Arg-447 to Gly) in Human Dihydrolipoamide Dehydrogenase of Patients with Neurological Deterioration