Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.2.1.13 (glyceraldehyde-3-phosphate dehydrogenase)
 6,511 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Excessive zinc influx may contribute to neuronal death after certain insults, including transient global ischemia. In light of evidence that levels of intracellular free Zn(2+) associated with neurotoxicity may be sufficient to inhibit glyceraldehyde-3-phosphate dehydrogenase (GAPDH), experiments were performed looking for reduced glycolysis and energy failure in cultured mouse cortical neurons subjected to lethal Zn(2+) exposure. As predicted, cultures exposed for 3-22 hr to 40 mixroM Zn(2+) developed an early increase in levels of dihydroxy-acetone phosphate (DHAP) and fructose 1,6-bisphosphate (FBP) and a progressive loss of ATP levels, followed by neuronal cell death; furthermore, addition of the downstream glycolytic substrate pyruvate to the bathing medium attenuated the fall in ATP and neuronal death. However, an alternative to direct Zn(2+) inhibition of GAPDH was raised by the observation that Zn(2+) exposure also induced an early decrease in nicotinamide-adenine dinucleotide (NAD(+)) levels, an event itself capable of inhibiting GAPDH. Favoring this indirect mechanism of GAPDH inhibition, the neuroprotective effects of pyruvate addition were associated with normalization of cellular levels of NAD(+), DHAP, and FBP. Zn(2+)-induced neuronal death was also attenuated by addition of the energy substrate oxaloacetate, the activator of pyruvate dehydrogenase, dichloroacetate, or the inhibitors of NAD(+) catabolism, niacinamide or benzamide. Acetyl carnitine, alpha-keto butyrate, lactate, and beta-hydroxy-butyrate did not attenuate Zn(2+)-induced neurotoxicity, perhaps because they could not regenerate NAD(+) or be used for energy production in the presence of glucose.
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PMID:Zinc-induced cortical neuronal death: contribution of energy failure attributable to loss of NAD(+) and inhibition of glycolysis. 1077 77

Corynebacterium glutamicum with the ability to simultaneously utilize glucose/pentose mixed sugars was metabolically engineered to overproduce shikimate, a valuable hydroaromatic compound used as a starting material for the synthesis of the anti-influenza drug oseltamivir. To achieve this, the shikimate kinase and other potential metabolic activities for the consumption of shikimate and its precursor dehydroshikimate were inactivated. Carbon flux toward shikimate synthesis was enhanced by overexpression of genes for the shikimate pathway and the non-oxidative pentose phosphate pathway. Subsequently, to improve the availability of the key aromatics precursor phosphoenolpyruvate (PEP) toward shikimate synthesis, the PEP: sugar phosphotransferase system (PTS) was inactivated and an endogenous myo-inositol transporter IolT1 and glucokinases were overexpressed. Unexpectedly, the resultant non-PTS strain accumulated 1,3-dihydroxyacetone (DHA) and glycerol as major byproducts. This observation and metabolome analysis identified glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-catalyzed reaction as a limiting step in glycolysis. Consistently, overexpression of GAPDH significantly stimulated both glucose consumption and shikimate production. Blockage of the DHA synthesis further improved shikimate yield. We applied an aerobic, growth-arrested and high-density cell reaction to the shikimate production by the resulting strain and notably achieved the highest shikimate titer (141g/l) and a yield (51% (mol/mol)) from glucose reported to date after 48h in minimal medium lacking nutrients required for cell growth. Moreover, comparable shikimate productivity could be attained through simultaneous utilization of glucose, xylose, and arabinose, enabling efficient shikimate production from lignocellulosic feedstocks. These findings demonstrate that C. glutamicum has significant potential for the production of shikimate and derived aromatic compounds.
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PMID:Metabolic engineering of Corynebacterium glutamicum for shikimate overproduction by growth-arrested cell reaction. 2755 83