Phosphates of the Vitamin B<sub>6</sub> Group. I. The Structure of Codecarboxylase

Heyl, Dorothea; Luz, Eileen; Harris, Stanton A.; Folkers, Karl

doi:10.1021/ja01151a126

Cited by 104 publications

(42 citation statements)

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“…Pyridoxal 5'-phosphate (PLP), one of the active forms of vitamin B 6 , was first identified in the mid forties as the cofactor required for the biochemical reaction of transamination [1]. Since then, PLP-dependent enzymes have been the subject of extensive research.…”

Section: Introductionmentioning

confidence: 99%

Pyridoxal 5-Phosphate Enzymes as Targets for Therapeutic Agents

Amadasi¹,

Bertoldi²,

Contestabile³

et al. 2007

CMC

178

157

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The vitamin B(6)-derived pyridoxal 5'-phosphate (PLP) is the cofactor of enzymes catalyzing a large variety of chemical reactions mainly involved in amino acid metabolism. These enzymes have been divided in five families and fold types on the basis of evolutionary relationships and protein structural organization. Almost 1.5% of all genes in prokaryotes code for PLP-dependent enzymes, whereas the percentage is substantially lower in eukaryotes. Although about 4% of enzyme-catalyzed reactions catalogued by the Enzyme Commission are PLP-dependent, only a few enzymes are targets of approved drugs and about twenty are recognised as potential targets for drugs or herbicides. PLP-dependent enzymes for which there are already commercially available drugs are DOPA decarboxylase (involved in the Parkinson disease), GABA aminotransferase (epilepsy), serine hydroxymethyltransferase (tumors and malaria), ornithine decarboxylase (African sleeping sickness and, potentially, tumors), alanine racemase (antibacterial agents), and human cytosolic branched-chain aminotransferase (pathological states associated to the GABA/glutamate equilibrium concentrations). Within each family or metabolic pathway, the enzymes for which drugs have been already approved for clinical use are discussed first, reporting the enzyme structure, the catalytic mechanism, the mechanism of enzyme inactivation or modulation by substrate-like or transition state-like drugs, and on-going research for increasing specificity and decreasing side-effects. Then, PLP-dependent enzymes that have been recently characterized and proposed as drug targets are reported. Finally, the relevance of recent genomic analysis of PLP-dependent enzymes for the selection of drug targets is discussed.

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Section: Introductionmentioning

confidence: 99%

Pyridoxal 5-Phosphate Enzymes as Targets for Therapeutic Agents

Amadasi¹,

Bertoldi²,

Contestabile³

et al. 2007

CMC

178

157

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“…grade wherever possible. Pyridoxal phosphate was prepared from pyridoxal hydrochloride by the method of Heyl et al (1951), and the resultant concentration determined by the method of Wada and Snell (1961). Whereas the addition of this pyridoxal phosphate to the homogenates of normal tissues resulted in no alteration of transaminase activity, its addition to the homogenates of some protein-depleted tissues caused an increase of activity.…”

Section: Methodsmentioning

confidence: 99%

Glutamate Transaminase Activity in Sheep Tissues, and the Response to Prolonged Protein Depletion

Masters¹,

Horgan²

1962

Aust. Jnl. Of Bio. Sci.

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SummaryThe glutamate transaminase activity of sheep tissues has been s~udied, along with the effect of such variables as age, sex, breed, and nutritional status of the animal. A wide range of normal activities has been found, with glutamic-oxaloacetic transaminase always more active than glutamic-pyruvic transaminase.Most activity centres in heart muscle, liver, kidney, and skeletal muscle; there appear to be sex and age differences, but little variation between breeds.Prolonged protein depletion has been shown to result in significant alterations of tissue transaminase activity, not only in the liver but also in myocardium, skeletal muscle, spleen, and pancreas. In addition, a cofactor deficiency was caused by the experimental diet.The implications of these findings have been discussed, in relation both to intermediary metabolism and to chemical pathology.

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“…As expected, ampicillin and an excess of NaF inhibited cell growth, whereas no effects were observed upon treatment with methionine ( To determine if DFM is toxic to organisms that endogenously express MGL, the growth inhibitory effects of DFM were studied on T. vaginalis, an anaerobic pathogen known to contain high levels of MGL activity [8,10]. The proposed intermediates, difluoromethanethiol and thioformyl fluoride were not observed by 19 F-NMR, since the species were likely to be too short lived for the observable timeframe of the experiments. Assuming that the transporter efflux between TFM and DFM in T. vaginalis does not significantly differ from the E. coli model, the growth inhibitory effects should reflect the potency of the compound between the two model organisms.…”

Section: Values Of Various Compounds For E Coli Cells Expressing Tvmmentioning

confidence: 98%

“…Briefly, the mixture consisted of 1 mmol of morpholine, 0.5 mmol of 1,1 -thiocarbonyl diimidazole and 0.5 mmol of triethylamine in CH 2 Cl 2 at 25 • C. The R f value on TLC was 0.39 in ethyl acetate/hexane (1:1). 34 The synthesis of MPAL was adapted from Heyl et al [19] and Johnston et al [20]. Briefly, the reaction mixture consisted of 1.5 mmol of N-dimethyl thioformamide and 1.5 mmol of morpholine in 5 ml of toluene, and the mixture was refluxed overnight at 100 • C. The R f value on TLC was 0.…”

Section: Synthesesmentioning

confidence: 99%

“…The positive controls were conducted in the presence of either ampicillin and NaF as inhibitors since ampicillin is known to inhibit bacterial growth, and fluoride ion can inhibit certain enzymes such as acid phosphatase [40]. 19 F-NMR studies demonstrated that TvMGL1 rapidly processed DFM as the 19 F-NMR signals rapidly disappeared in the presence of enzyme (Figure 2d). DFM was found to be active against this pathogen, approximately 20-fold less potent than the clinically approved drug metronidazole (Table 2 and Supplementary Figures S5e and S5f), and 2-fold less potent than the EC 50 value obtained in the E. coli model ( Table 2).…”

Section: Values Of Various Compounds For E Coli Cells Expressing Tvmmentioning

confidence: 99%

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Mechanistic studies on the enzymatic processing of fluorinated methionine analogues by Trichomonas vaginalis methionine γ-lyase

Moya

Westrop

Coombs

et al. 2011

Biochemical Journal

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TFM (L-trifluoromethionine), a potential prodrug, was reported to be toxic towards human pathogens that express MGL (L-methionine γ-lyase; EC 4.4.1.11), a pyridoxal phosphate-containing enzyme that converts L-methionine into α-oxobutyrate, ammonia and methyl mercaptan. It has been hypothesized that the extremely reactive thiocarbonyl difluoride is produced when the enzyme acts upon TFM, resulting in cellular toxicity. The potential application of the fluorinated thiomethyl group in other areas of biochemistry and medicinal chemistry requires additional studies. Therefore a detailed investigation of the theoretical and experimental chemistry and biochemistry of these fluorinated groups (CF₃S⁻ and CF₂HS⁻) has been undertaken to trap and identify chemical intermediates produced by enzyme processing of molecules containing these fluorinated moieties. TvMGL (MGL from Trichomonas vaginalis) and a chemical model system of the reaction were utilized in order to investigate the cofactor-dependent activation of TFM and previously uninvestigated DFM (L-difluoromethionine). The differences in toxicity between TFM and DFM were evaluated against Escherichia coli expressing TvMGL1, as well as the intact human pathogen T. vaginalis. The relationship between the chemical structure of the reactive intermediates produced from the enzymatic processing of these analogues and their cellular toxicity are discussed.

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Phosphates of the Vitamin B₆ Group. I. The Structure of Codecarboxylase

Cited by 104 publications

References 0 publications

Pyridoxal 5-Phosphate Enzymes as Targets for Therapeutic Agents

Pyridoxal 5-Phosphate Enzymes as Targets for Therapeutic Agents

Glutamate Transaminase Activity in Sheep Tissues, and the Response to Prolonged Protein Depletion

Mechanistic studies on the enzymatic processing of fluorinated methionine analogues by Trichomonas vaginalis methionine γ-lyase

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Phosphates of the Vitamin B6 Group. I. The Structure of Codecarboxylase

Cited by 104 publications

References 0 publications

Pyridoxal 5-Phosphate Enzymes as Targets for Therapeutic Agents

Pyridoxal 5-Phosphate Enzymes as Targets for Therapeutic Agents

Glutamate Transaminase Activity in Sheep Tissues, and the Response to Prolonged Protein Depletion

Mechanistic studies on the enzymatic processing of fluorinated methionine analogues by Trichomonas vaginalis methionine γ-lyase

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Phosphates of the Vitamin B₆ Group. I. The Structure of Codecarboxylase