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

The paper provides an interdisciplinary evaluation of the etiology, pathogenesis, and experimental treatments of retinitis pigmentosa (RP). It addresses a 10-year controversy concerning the rate of progression of RP. One laboratory has estimated remaining visual field to be lost at a rate of 4.6% per year, whereas another laboratory estimates loss at 16-18%. This large discrepancy and lack of consensus needs resolution, since they pose serious statistical and operational problems for evaluating experimental treatment approaches to RP. The resolution of the controversy offered in the paper is based on a model of RP in which the initial rate of loss of visual field (the induction phase) is much slower than the subsequent logarithmic first-order rate of loss. The rationale for this kinetic model is that loss of mitochondrial function, possibly due to RP-genetically-related radical processes, has to reach a critical threshold value before the mitochondrial trigger of programmed cell death or apoptosis (i.e., the release of mitochondrial cytochrome c by the opening of the permeability transition pore, PTP) can be activated by an encounter with a second, but kinetically constant causative stress factor - most likely a light-stress-related factor. In its essential (two-causal) aspects, this kinetic model for RP is identical to the kinetic theories that have been proposed for the Gombertz human mortality plot. The described kinetic model for RP provides a solution to the visual field-loss controversy, since the first study was performed with a population containing a greater number of patients in the slow stage of RP than the second. Another objective of the investigation was to identify possible mechanisms of how the numerous genetic mutations in the rods of RP patients could give rise to damaging free-radical reactions capable of triggering apoptosis through their adverse effects on mitochondrial function. Another reason for focusing on radical reactions in RP was to provide a rationale for the proposed use of an extensive array of antioxidants and nutritional supplements for stemming progression of RP. In particular, the investigation focuses on saving cone-dependent central vision, i.e. on saving cells not affected by the genetic problems of the rods, but cells which can become lethally damaged by a spill-over of radicals and related harmful chemical reactions occurring in the rods.The third objective deals with the development of a rationale for a new strategy for retarding RP. This involves the use of desmethyldeprenyl, a metabolite of the anti-Parkinson's drug, deprenyl. The rationale is, in part, based on an observation that desmethyldeprenyl exerts antiapoptotic activities in a variety of neurodegenerative disorders. The protective mechanism involves the overexpression of the anti-apoptotic bcl-2 gene, leading to higher concentrations of bcl-2 proteins, which by binding to mitochondria inhibits the trigger mechanism of apoptosis - the opening of PTP and release of cytochrome C. At the same time, desmethyldeprenyl causes the underexpression of the pro-apoptotic bax gene, which via bax proteins facilitates the opening of the PTP. Both the anti-apoptotic and pro-apoptotic mechanisms appear to be mediated by the binding of desmethyldeprenyl to glyceraldehyde-3-phosphate dehydrogenase. Antiapoptotic effects can also be generated by the parent compound, deprenyl, when this is used daily in low concentrations of 1-2 mg/100 kg body weight. Under these conditions, it appears that the anti-apoptotic metabolite, desmethyldeprenyl, predominates over the pro-apoptotic metabolites of deprenyl, l -methamphetamine and l -amphetamine. Methamphetamine is not formed if desmethyldeprenyl is administered directly and thus could give desmethyldeprenyl a pharmacokinetic advantage over deprenyl. (ABSTRACT TRUNCATED)
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PMID:Etiology, pathogenesis, and experimental treatment of retinitis pigmentosa. 1085 93

Erythrocyte glyceraldehyde-3-phosphate dehydrogenase (G3PD), is a glycolytic enzyme normally inhibited upon binding to the anion transporter Band 3 and activated when free in the cytosol. We have previously reported that ferric protoporphyrin IX (FP) enhances G3PD activity in human erythrocytes (RBC). This could be due to two mechanisms considered in this work: Band 3 tyrosine phosphorylation or oxidative damage of specific G3PD binding sites in the membrane. In both cases binding of G3PD to the membrane would be prevented, leading to the enhancement of G3PD activity. Here, we show that FP induces a dose- and time-dependent phosphorylation of tyrosine 8 and 21 of Band 3, as confirmed by the recruitment of SHP2 phosphatase to the membrane. It appears that Band 3 phosphorylation is due to the oxidation of critical sulfydryl groups of a membrane phosphatase (PTP). Data on membrane localization, Mg2+ dependence, sensitivity to thiol oxidizing agents and protection by N-acetylcysteine (NAC) and DTT strongly suggest the involvement of PTP1B, the major PTP of human RBC associated to and acting on Band 3. However, FP activates G3PD even when Band 3 phosphorylation is inhibited, therefore phosphorylation is not the mechanism underlying G3PD activation by FP. The capacity of NAC of counteracting the stimulatory activity of FP, supports the hypothesis that FP might induce the oxidative damage of specific G3PD binding sites in the membrane, causing the displacement of the enzyme into the cytosol and/or the release from its binding site and therefore its activation.
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PMID:Modulation of glyceraldehyde 3 phosphate dehydrogenase activity and tyr-phosphorylation of Band 3 in human erythrocytes treated with ferriprotoporphyrin IX. 1771 94

Molecular genetic approaches are playing an increasing role in conservation science by identifying biodiversity that may not be evident by morphology-based taxonomy and systematics. So-called cryptic species are particularly prevalent in freshwater environments, where isolation of dispersal-limited species, such as crayfishes, within dendritic river networks often gives rise to high intra- and inter-specific genetic divergence. We apply here a multi-gene molecular approach to investigate relationships among extant species of the crayfish genus Pacifastacus, representing the first comprehensive phylogenetic study of this taxonomic group. Importantly, Pacifastacus includes both the widely invasive signal crayfish Pacifastacus leniusculus, as well as several species of conservation concern like the Shasta crayfish Pacifastacus fortis. Our analysis used 83 individuals sampled across the four extant Pacifastacus species (omitting the extinct Pacifastacus nigrescens), representing the known taxonomic diversity and geographic distributions within this genus as comprehensively as possible. We reconstructed phylogenetic trees from mitochondrial (16S, COI) and nuclear genes (GAPDH), both separately and using a combined or concatenated dataset, and performed several species delimitation analyses (PTP, ABGD, GMYC) on the COI phylogeny to propose Primary Species Hypotheses (PSHs) within the genus. All phylogenies recovered the genus Pacifastacus as monophyletic, within which we identified a range of six to 21 PSHs; more abundant PSHs delimitations from GMYC and ABGD were always nested within PSHs delimited by the more conservative PTP method. Pacifastacus leniusculus included the majority of PSHs and was not monophyletic relative to the other Pacifastacus species considered. Several of these highly distinct P. leniusculus PSHs likely require urgent conservation attention. Our results identify research needs and conservation priorities for Pacifastacus crayfishes in western North America, and may inform better understanding and management of P. leniusculus in regions where it is invasive, such as Europe and Japan.
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PMID:Phylogenetic species delimitation for crayfishes of the genus Pacifastacus. 2711 75

In many lichen-forming fungi, molecular phylogenetic analyses lead to the discovery of cryptic species within traditional morphospecies. However, in some cases, molecular sequence data also questions the separation of phenotypically characterised species. Here we apply an integrative taxonomy approach - including morphological, chemical, molecular, and distributional characters - to re-assess species boundaries in a traditionally speciose group of hair lichens, Bryoria sect. Implexae. We sampled multilocus sequence and microsatellite data from 142 specimens from a broad intercontinental distribution. Molecular data included DNA sequences of the standard fungal markers ITS, IGS, GAPDH, two newly tested loci (FRBi15 and FRBi16), and SSR frequencies from 18 microsatellite markers. Datasets were analysed with Bayesian and maximum likelihood phylogenetic reconstruction, phenogram reconstruction, STRUCTURE Bayesian clustering, principal coordinate analysis, haplotype network, and several different species delimitation analyses (ABGD, PTP, GMYC, and DISSECT). Additionally, past population demography and divergence times are estimated. The different approaches to species recognition do not support the monophyly of the 11 currently accepted morphospecies, and rather suggest the reduction of these to four phylogenetic species. Moreover, three of these are relatively recent in origin and cryptic, including phenotypically and chemically variable specimens. Issues regarding the integration of an evolutionary perspective into taxonomic conclusions in species complexes, which have undergone recent diversification, are discussed. The four accepted species, all epitypified by sequenced material, are Bryoria fuscescens, B. glabra, B. kockiana, and B. pseudofuscescens. Ten species rank names are reduced to synonymy. In the absence of molecular data, they can be recorded as the B. fuscescens complex. Intraspecific phenotype plasticity and factors affecting the speciation of different morphospecies in this group of Bryoria are outlined.
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PMID:Evaluating methodologies for species delimitation: the mismatch between phenotypes and genotypes in lichenized fungi (Bryoria sect. Implexae, Parmeliaceae). 3155 15