Pyridoxal phosphate. I. Phosphonic acid analogs of pyridoxal phosphate. Synthesis via Wittig reactions and enzymic evaluation

Hullar, T. L.

doi:10.1021/jm00301a016

Cited by 43 publications

(25 citation statements)

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“…2-(4-Formyl-3-hydroxy-2-methyl-pyrid-5-yl)ethylphosphonic acid (22): The title compound was synthesized by the reported method [Hullar, 1969] with minor modification of reagents. 1 H-NMR (D 2 O + NaOD) δ 1.47-1.58 (2H, m, CH 2 ), 2.22, (3H, s, CH 3 ), 2.75-2.98 (2H, m, CH 2 ), 7.29(1H, s, H6), 10.30 (1H, s, CHO); 31 P-NMR (D 2 O + NaOD) δ 21.41-21.71 (m, phosphonic acid).…”

Section: -(4-formyl-3-hydroxy-2-methyl-pyrid-5-yl)propylphosphonic Acidmentioning

confidence: 99%

“…5-trans-Vinyl and 5-ethyl phosphonate derivatives, 26 and 22, were synthesized by the reported procedures [Hullar, 1969] with minor modification of reagents. 5-Allyl and 5-propyl phosphonic acid derivatives were prepared through a Wittig reaction of the aldehyde group [Tomita et al, 1966] in 40 leading to the trans-vinyl carboxylic acid ester, 41.…”

Section: Synthesismentioning

confidence: 99%

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Synthesis and structure-activity relationships of pyridoxal-6-arylazo-5?-phosphate and phosphonate derivatives as P2 receptor antagonists

et al. 1998

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Novel analogs of the P2 receptor antagonist pyridoxal‐5′‐phosphate‐6‐phenylazo‐2′,4′‐disulfonate (PPADS) were synthesized. Modifications were made through functional group substitution on the sulfophenyl ring and at the phosphate moiety through the inclusion of phosphonates, demonstrating that a phosphate linkage is not required for P2 receptor antagonism. Substituted 6‐phenylazo and 6‐naphthylazo derivatives were also evaluated. Among the 6‐phenylazo derivatives, 5′‐methyl, ethyl, propyl, vinyl, and allyl phosphonates were included. The compounds were tested as antagonists at turkey erythrocyte and guinea‐pig taenia coli P2Y1 receptors, in guinea‐pig vas deferens and bladder P2X1 receptors, and in ion flux experiments by using recombinant rat P2X2 receptors expressed in Xenopus oocytes. Competitive binding assay at human P2X1 receptors in differentiated HL‐60 cell membranes was carried out by using [35S]ATP‐γ‐S. A 2′‐chloro‐5′‐sulfo analog of PPADS (C14H12O9N3ClPSNa), a vinyl phosphonate derivative (C15H12O11N3PS2Na3), and a naphthylazo derivative (C18H14O12N3PS2Na2), were particularly potent in binding to human P2X1 receptors. The potencies of phosphate derivatives at P2Y1 receptors were generally similar to PPADS itself, except for the p‐carboxyphenylazo phosphate derivative C15H13O8N3PNa and its m‐chloro analog C15H12O8N3ClPNa, which were selective for P2X vs. P2Y1 receptors. C15H12O8N3ClPNa was very potent at rat P2X2 receptors with an IC50 value of 0.82 μM. Among the phosphonate derivatives, [4‐formyl‐3‐hydroxy‐2‐methyl‐6‐(2‐chloro‐5‐sulfonylphenylazo)‐pyrid‐5‐yl]methylphosphonic acid (C14H12O8N3ClPSNa) showed high potency at P2Y1 receptors with an IC50 of 7.23 μM. The corresponding 2,5‐disulfonylphenyl derivative was nearly inactive at turkey erythrocyte P2Y1 receptors, whereas at recombinant P2X2 receptors had an IC50 value of 1.1 μM. An ethyl phosphonate derivative (C15H15O11N3PS2Na3), whereas inactive at turkey erythrocyte P2Y1 receptors, was particularly potent at recombinant P2X2 receptors. Drug Dev. Res. 45:52–66, 1998. Published 1998 Wiley‐Liss, Inc.

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Section: -(4-formyl-3-hydroxy-2-methyl-pyrid-5-yl)propylphosphonic Acidmentioning

confidence: 99%

Section: Synthesismentioning

confidence: 99%

Synthesis and structure-activity relationships of pyridoxal-6-arylazo-5?-phosphate and phosphonate derivatives as P2 receptor antagonists

et al. 1998

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“…This aldamine derivative (a secondary amine) can only confirm the presence or absence of a phosphate ionisation in the measured pH range. The phosphonate derivative of the natural cofactor was chosen for several reasons: (a) in free solution, this cofactor analogue and its model Schiff bases display a pK, of 7.4 [16], compared to that of 6.2 for pyridoxal phosphate and its model Schin'bases [lo]; (b) the pH dependence of the 311) chemical shift for pyridoxal 5'-deoxymethylenephosphonate (PDMP) is in opposite field direction when compared with pyridoxal phosphate; (c) pyridoxal 5'-deoxymethylenephosphonate bound to aspartate aminotransferase causes thc pK of the cofactor-analogue -Lys258 Schiff base to drop to the anomalously low value of 3.7, as measured by optical absorption spectroscopy [17]. Therefore, it should be particularly easy to differentiate betwecn deprotonation of the phosphonate and deprotonation of the Schiff base in apoaspartate aminotransferase which has been reconstituted with PDMP.…”

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confidence: 99%

Evidence that ³¹P NMR is a sensitive indicator of small conformational changes in the coenzyme of aspartate aminotransferase

Schnackerz

Wahler

Vincent

et al. 1989

European Journal of Biochemistry

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The pH dependence of 'P-NMR spectra of pig cytosolic aspartate aminotransferase, containing either N-(5'-phosphopyridoxy1)-L-aspartate or pyridoxal 5'-deoxymethylenephosphonate in place of the normal coenzyme pyridoxal 5'-phosphate, has been analysed. The chemical shifts of phosphopyridoxylaspartate and of pyridoxal 5'-deoxymethylenephosphonate model Schiff base in frce solution show pK values of 6.3 and 7.4, attributable to the second deprotonation step of phosphate and phosphonate, respectively. However, these compounds behave very differently when bound to apoaspartate aminotransferase. 31P-NMR spectra of these enzyme derivatives indicate that the phosph(on)ate group remains dianionic throughout the pH range 4 -8.5. A clear correlation between apparent pK values obtained from spectrophotometric titration of the coenzyme chromophore and those obtained by 3 1 P N M R indicates that the 5ame ionisation is being reported by both methods. The data are interpreted, on the basis of available crystallographic structures of chicken mitochondrial aspartate aminotransferase, to indicate that in each case the alteration in 31P chemical shift results from a conformational change in the coenzyme 5' side chain, in which one of the structures involves a near-eclipsed pair of bonds. Such a stressed conformation produces slight alterations in bond angles around the phosphorus atom, which in turn cause the observed change in 31P chemical shift. The evidence is taken to indicate that in this case 31P NMR is a sensitive reporter of stress in enzyme-bound pyridoxal 5'-phosphate and its derivatives.Aspartate aminotransferase is the most extensively studied representative of the large family of pyridoxal-phosphatedependent enzymes that function in amino acid metabolism [l, 21. X-Ray crystallographic studies of native and inhibited forms of both the mitochondria1 and the cytosolic isozyme have revealed their nearly identical spatial structures and active sites and led to proposals for the stereochemistry of their catalytic action [3 -61.One highly relevant characteristic influencing the catalytic behaviour of an enzyme is the charge distribution in its active site. In aspartate aminotransferase, an important uncertainty which still remains is the charge on the coenzyme phosphate during the catalytic cycle. In recent years attempts have been made to determine this charge by 'P-NMR spectroscopy. Martinez-Carri6n [7] was the first to apply this technique to cytosolic aspartate aminotransferase. From his data he concludcd that in both the pyridoxal phosphate and the pyridoxaminc phosphate forms of cytosolic aspartate aminotransferase the cofactor phosphate group remains fully ionized in the pH range 5.6-9.2. However, in later experiments with the mitochondrial isozyme, a pH-dependent chemical shift was observed for the pyridoxal phosphate holoenzyme with, for example, a pK, of 6.3 and an amplitude of 1.3 ppm for the Correspondence to J. N.

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“…The two phosphonates 11 and 12, with dimensions and charge characteristics similar to those of pyridoxal-P, have substantial catalytic activity (52,53). On the other hand, analogs of similar steric properties but having only a single negative charge in the side chain, for example, the monomethyl ester of pyridoxal-P, have a very low activity, usually less than 1% of that of pyridoxal-P (54,55).…”

Section: Hc=o (11) Y --Chandhpo" (12) Y P -Ch----chpol'-(tram)mentioning

confidence: 99%

Tautomerism in Pyridoxal Phosphate and in Enzymatic Catalysis

Metzler

1979

Advances in Enzymology - And Related Areas of Molecular Biology

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Pyridoxal phosphate. I. Phosphonic acid analogs of pyridoxal phosphate. Synthesis via Wittig reactions and enzymic evaluation

Cited by 43 publications

References 1 publication

Synthesis and structure-activity relationships of pyridoxal-6-arylazo-5?-phosphate and phosphonate derivatives as P2 receptor antagonists

Synthesis and structure-activity relationships of pyridoxal-6-arylazo-5?-phosphate and phosphonate derivatives as P2 receptor antagonists

Evidence that ³¹P NMR is a sensitive indicator of small conformational changes in the coenzyme of aspartate aminotransferase

Tautomerism in Pyridoxal Phosphate and in Enzymatic Catalysis

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Pyridoxal phosphate. I. Phosphonic acid analogs of pyridoxal phosphate. Synthesis via Wittig reactions and enzymic evaluation

Cited by 43 publications

References 1 publication

Synthesis and structure-activity relationships of pyridoxal-6-arylazo-5?-phosphate and phosphonate derivatives as P2 receptor antagonists

Synthesis and structure-activity relationships of pyridoxal-6-arylazo-5?-phosphate and phosphonate derivatives as P2 receptor antagonists

Evidence that 31P NMR is a sensitive indicator of small conformational changes in the coenzyme of aspartate aminotransferase

Tautomerism in Pyridoxal Phosphate and in Enzymatic Catalysis

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Evidence that ³¹P NMR is a sensitive indicator of small conformational changes in the coenzyme of aspartate aminotransferase