Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In plants, excess cellular lysine (Lys) is catabolized into glutamic acid and acetyl-coenzyme A; yet, it is still not clear whether this pathway has other functions in addition to balancing Lys levels. To address this issue, we examined the effects of stress-related hormones, abscisic acid (ABA), and jasmonate, as well as various metabolic signals on the production of the mRNA and polypeptide of the bifunctional Lys-ketoglutarate reductase (LKR)/saccharopine dehydrogenase (SDH) enzyme, which contains the first two linked enzymes of Lys catabolism. The level of LKR/SDH was strongly enhanced by ABA, jasmonate, and sugar starvation, whereas excess sugars and nitrogen starvation reduced its level; thus this pathway appears to fulfill multiple functions in stress-related and carbon/nitrogen metabolism. Treatments with combination of hormones and/or metabolites, as well as use of ABA mutants in conjunction with the tester sugars mannose and 3-O-methyl-glucose further supported the idea that the hormonal and metabolic signals apparently operate through different signal transduction cascades. The stimulation of LKR/SDH protein expression by ABA is regulated by a signal transduction cascade that contains the ABI1-1 and ABI2-1 protein phosphatases. By contrast, the stimulation of LKR/SDH protein expression by sugar starvation is regulated by the hexokinase-signaling cascade in a similar manner to the repression of many photosynthetic genes by sugars. These findings suggest a metabolic and mechanistic link between Lys catabolism and photosynthesis-related metabolism in the regulation of carbon/nitrogen partitioning.
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PMID:Synthesis of the Arabidopsis bifunctional lysine-ketoglutarate reductase/saccharopine dehydrogenase enzyme of lysine catabolism is concertedly regulated by metabolic and stress-associated signals. 1457 81

Vitamin K epoxide reductase (VKOR) recycles reduced vitamin K, which is used subsequently as a co-factor in the gamma-carboxylation of glutamic acid residues in blood coagulation enzymes. VKORC1, a subunit of the VKOR complex, has recently been shown to possess this activity. Here, we show that VKORC1 is a member of a large family of predicted enzymes that are present in vertebrates, Drosophila, plants, bacteria and archaea. Four cysteine residues and one residue, which is either serine or threonine, are identified as likely active-site residues. In some plant and bacterial homologues the VKORC1 homologous domain is fused with domains of the thioredoxin family of oxidoreductases. These might reduce disulfide bonds of VKORC1-like enzymes as a prerequisite for their catalytic activities.
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PMID:Vitamin K epoxide reductase: homology, active site and catalytic mechanism. 1527 81

Previous studies on mammalian peroxidases and cytochrome P450 family 4 enzymes have shown that a carboxylic group positioned close to a methyl group of the prosthetic heme is required for the formation of a covalent link between a protein carboxylic acid side chain and the heme. To determine whether there are additional requirements for covalent bond formation in the P450 enzymes, a glutamic acid or an aspartic acid has been introduced into P450(cam) close to the heme 5-methyl group. Spectroscopic and kinetic studies of the resulting G248E and G248D mutants suggest that the carboxylate group coordinates with the heme iron atom, as reported for a comparable P450(BM3) mutant [Girvan, H. M., Marshall, K. R., Lawson, R. J., Leys, D., Joyce, M. G., Clarkson, J., Smith, W. E., Cheesman, M. R., and Munro, A. W. (2004) J. Biol. Chem. 279, 23274-23286]. The two P450(cam) mutants have low catalytic activity, but in contrast to the P450(BM3) mutant, incubation of the G248E (but not G248D) mutant with camphor, putidaredoxin, putidaredoxin reductase, and NADH results in partial covalent binding of the heme to the protein. No covalent attachment is observed in the absence of camphor or any of the other reaction components. Pronase digestion of the G248E P450(cam) mutant after covalent attachment of the heme releases 5-hydroxyheme, establishing that the heme is covalently attached through its 5-methyl group as predicted by in silico modeling. The results establish that a properly positioned carboxyl group is the sole requirement for autocatalytic formation of a heme-protein link in P450 enzymes, but also show that efficient covalent binding requires placement of the carboxyl close to the methyl but in a manner that prevents strong coordination to the iron atom.
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PMID:The P450cam G248E mutant covalently binds its prosthetic heme group. 1575 86

Sufiredoxin (Srx) is a sulfinic acid reductase, a recently identified eukaryotic enzyme, which is involved in the reduction of the hyperoxidized sulfinic acid form of the catalytic cysteine of 2-Cys peroxiredoxins (Prx). This reaction contributes to the oxidative stress response and H2O2 mediated signaling. We show that Srx has significant sequence and structural similarity to a functionally unrelated protein, ParB, a DNA-binding protein with a helix-turn-helix (HTH) domain which is involved in chromosome partitioning in bacteria. Sequence comparison and phylogenetic analysis of the Srx and ParB protein families suggest that Srx evolved via truncation of ParB, which removed the entire C-terminal half of the protein, including the HTH domain, and a substitution of cysteine for a glutamic acid in a highly conserved structural motif of ParB. The latter substitution apparently created the sulfinic acid reductase catalytic site. Evolution of a redox enzyme from a DNA-binding protein, with retention of highly significant sequence similarity, is unusual, even when compared to functional switches accompanying recruitment of other prokaryotic proteins for new functions in eukaryotes.
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PMID:Evolution of eukaryotic cysteine sulfinic acid reductase, sulfiredoxin (Srx), from bacterial chromosome partitioning protein ParB. 1591 47

Heme-copper oxygen reductases catalyze proton translocation across the cellular membrane; this takes place during the reaction of oxygen to water. We demonstrate with attenuated total reflection-Fourier transform infrared (ATR-FTIR) difference spectroscopy that a tyrosine residue of the oxygen reductase from the thermohalophilic Rhodothermus marinus becomes deprotonated in the transition from the oxidized state to the catalytic intermediate ferryl state P(M). This tyrosine residue is most probably Y256, the helix VI tyrosine residue proposed to substitute for the D-channel glutamic acid that is absent in this enzyme. Comparison with the mitochondrial like oxygen reductase from Rhodobacter sphaeroides suggests that proton transfer from a strategically situated donor to the active site is a crucial step in the reaction mechanism of oxygen reductases.
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PMID:A tyrosine residue deprotonates during oxygen reduction by the caa3 reductase from Rhodothermus marinus. 1646 22

Acetohydroxamate (AHA) and aminooxyacetate (AOA) were found to be potent inhibitors of purified NADPH(NADH)-dependent glyoxylate reductase from spinach (Spinacia oleracea) leaves. AHA was a noncompetitive (ro mixed) inhibitor of the NADPH-dependent activity of the reductase with a K(i) of 0.33 millimolar. With NADH serving as a cofactor, AHA preferentially bound to the same form of the enzyme as glyoxylate, exhibiting a K(i) of 0.31 millimolar. Glycine hydroxamate and l-glutamic acid-gamma-hydroxamate were also inhibitory, but to a lesser extent than AHA. Inhibition by AOA (K(i) of 1.8 millimolar) was enhanced by increased concentrations of glyoxylate, indicating that the inhibitor preferentially reacted with the glyoxylate-bound form of the enzyme. Glycidate, an effector of glycolate metabolism in leaves, was found to be a much weaker inhibitor of the enzyme with a K(i) of 21 millimolar. While the inhibition by both AHA and AOA was fully reversible, glycidate acted as a tight-binding inhibitor. These findings are discussed with respect to the use of AHA, AOA, and glycidate as inhibitors of photorespiratory carbon metabolism in leaves. Caution is recommended in the use of these inhibitors with intact tissue experiments due to their lack of specificity.
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PMID:Inhibition of Spinach Leaf NADPH(NADH)-Glyoxylate Reductase by Acetohydroxamate, Aminooxyacetate, and Glycidate. 1666 91

NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a member of the short-chain dehydrogenase/reductase (SDR) family, catalyzes the first step in the catabolic pathways of prostaglandins and lipoxins. This enzyme oxidizes the C-15 hydroxyl group of prostaglandins and lipoxins to produce 15-keto metabolites which exhibit greatly reduced biological activities. A three-dimensional (3D) structure of 15-PGDH based on the crystal structures of the levodione reductase and tropinone reductase-II was generated and used for docking study with NAD+ coenzyme and PGE2 substrate. Three well-conserved residues among SDR family which correspond to Ser-138, Tyr-151, and Lys-155 of 15-PGDH have been shown to participate in the catalytic reaction. Based on the molecular interactions observed from 3D structure of 15-PGDH, we further propose that Gln-148 in 15-PGDH is important in properly positioning the 15-hydroxyl group of PGE2 by hydrogen bonding with the side-chain oxygen atom of Gln-148. This residue is found to be less conserved and replaceable by glutamyl, histidinyl, and asparaginyl residues in SDR family. Accordingly, site-directed mutagenesis of Gln-148 of 15-PGDH to alanine, glutamic acid, histidine, and asparagine (Q148A, Q148E, Q148H, and Q148N) was carried out. The activity of mutant Q148A was not detectable, whereas those of mutants Q148E, Q148H, and Q148N were comparable to or higher than the wild type. This indicates that the side-chain oxygen or nitrogen atom at position 148 of 15-PGDH plays an important role in anchoring C-15 hydroxyl group of PGE2 through hydrogen bonding for catalytic reaction.
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PMID:Role of glutamine 148 of human 15-hydroxyprostaglandin dehydrogenase in catalytic oxidation of prostaglandin E2. 1682 55

Active-site models of bacterial nitric oxide reductase (NOR) featuring a heme Fe and a trisimidazole- and glutaric acid-bound non-heme Fe (Fe(B)) have been synthesized. These models closely replicate the proposed active site of native NORs. Examination of these models shows that the glutamic acid mimic is required for both Fe(B) retention in the distal binding site and proper modulation of the redox potentials of both the heme and non-heme Fe's.
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PMID:Active-site models of bacterial nitric oxide reductase featuring tris-histidyl and glutamic acid mimics: influence of a carboxylate ligand on Fe(B) binding and the heme Fe/Fe(B) redox potential. 1696 46

Warfarin is a widely prescribed anticoagulant for thromboembolic disorders and exhibits wide inter-individual differences in its pharmacodynamic effects. Warfarin exerts its anticoagulant effect by inhibiting the enzymatic activity of vitamin K 2,3-epoxide reductase complex, subunit 1 (VKORC1) which regenerates reduced vitamin K as an essential cofactor for the post-translational gamma-carboxylation of glutamic acid residues on coagulation factors II, VII, IX and X, and the anticoagulant proteins C, S and Z. Recent studies have shown polymorphisms in genes involved in the uptake of vitamin K (apolipoprotein E [ApoE]), reduction of vitamin K 2,3-epoxide (VKORC1), metabolism of warfarin (cytochrome P450 2C9 [CYP2C9]), and gamma carboxylation (gamma-glutamyl carboxylase [GGCX]) to influence the pharmacokinetics and pharmacodynamics of warfarin in patients from different ethnic backgrounds, resulting in variable warfarin dose requirements. Understanding the causal relationship of these polygenic influences on warfarin dose requirements in patients of different ethnicity may be vital in reducing inter-patient variability and optimising anticoagulant therapy.
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PMID:Pharmacogenetics of target genes across the warfarin pharmacological pathway. 1711 95

Co-ordination of catalytic Zn2+ in sorbitol/xylitol dehydrogenases of the medium-chain dehydrogenase/reductase superfamily involves direct or water-mediated interactions from a glutamic acid residue, which substitutes a homologous cysteine ligand in alcohol dehydrogenases of the yeast and liver type. Glu154 of xylitol dehydrogenase from the yeast Galactocandida mastotermitis (termed GmXDH) was mutated to a cysteine residue (E154C) to revert this replacement. In spite of their variable Zn2+ content (0.10-0.40 atom/subunit), purified preparations of E154C exhibited a constant catalytic Zn2+ centre activity (kcat) of 1.19+/-0.03 s(-1) and did not require exogenous Zn2+ for activity or stability. E154C retained 0.019+/-0.003% and 0.74+/-0.03% of wild-type catalytic efficiency (kcat/K(sorbitol)=7800+/-700 M(-1) x s(-1)) and kcat (=161+/-4 s(-1)) for NAD+-dependent oxidation of sorbitol at 25 degrees C respectively. The pH profile of kcat/K(sorbitol) for E154C decreased below an apparent pK of 9.1+/-0.3, reflecting a shift in pK by about +1.7-1.9 pH units compared with the corresponding pH profiles for GmXDH and sheep liver sorbitol dehydrogenase (termed slSDH). The difference in pK for profiles determined in 1H2O and 2H2O solvent was similar and unusually small for all three enzymes (approximately +0.2 log units), suggesting that the observed pK in the binary enzyme-NAD+ complexes could be due to Zn2+-bound water. Under conditions eliminating their different pH-dependences, wild-type and mutant GmXDH displayed similar primary and solvent deuterium kinetic isotope effects of 1.7+/-0.2 (E154C, 1.7+/-0.1) and 1.9+/-0.3 (E154C, 2.4+/-0.2) on kcat/K(sorbitol) respectively. Transient kinetic studies of NAD+ reduction and proton release during sorbitol oxidation by slSDH at pH 8.2 show that two protons are lost with a rate constant of 687+/-12 s(-1) in the pre-steady state, which features a turnover of 0.9+/-0.1 enzyme equivalents as NADH was produced with a rate constant of 409+/-3 s(-1). The results support an auxiliary participation of Glu154 in catalysis, and possible mechanisms of proton transfer in sorbitol/xylitol dehydrogenases are discussed.
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PMID:Catalytic mechanism of Zn2+-dependent polyol dehydrogenases: kinetic comparison of sheep liver sorbitol dehydrogenase with wild-type and Glu154-->Cys forms of yeast xylitol dehydrogenase. 1734 68


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