Pyridoxal analogues

The molecule is a chiral analogue of pyridoxamine and transamination occurs chemically by a mechanism similar to the biological one described in the chapter (pp. 1384-6). The zinc holds the molecule in a fixed conformation during reaction. The key step is the protonation of the enamine as that produces the new chiral centre. If the chain is across the top of the ring, protonation occurs preferentially from underneath. Hydrolysis gives the new amino acid (Phe) and the pyridoxal analogue, which can be recycled by reductive amination via the oxime. 

Kuzuhara H, Iwata M, Emoto S (1977) Synthesis of a chiral pyridoxal analogue as a potential catalyst for stereospecific nonenzymatic reactions. J Am Chem Soc 99 4173-4175 Kuzuhara H, Komatsu T, Emoto S (1978) Synthesis of a chiral pyridox-amine analog and nonenzymatic stereoselective transamination. Tetrahedron Lett 3563-3566... 

Over 250 analogues of the B vitamers have been reported (11,100). Nearly all have low vitamin B activity and some show antagonism. Among these are the 4-deshydroxy analogue, pyridoxine 4-ethers, and 4-amino-5-hydroxymeth5i-2-methyipyrimidine, a biosynthetic precursor to thiamine. StmcturaHy unrelated antagonists include dmgs such as isoniazid, cycloserine, and penicillamine, which are known to bind to pyridoxal enzyme active sites (4). 

Pyridoxal Phosphate.—Analogues of pyridoxal and pyridoxamine 5 -phosphates have frequently been used to probe the size and shape of the active sites of a number of enzymes. For example, the apoenzyme of a tryptophanase from Bacillus alvei will bind pyridoxal 5 -phosphate as well as the 2-nor, 2 -methyl, 2 -hydroxy, 6-methyl, and A-oxide analogues.27 No analogue that has been modified at C-4 binds to the enzyme, confirming the absolute requirement for Schiff-base formation between the... 

This method does not seem to be applicable if R is aromatic, as would be necessary to make the arsonomethyl analogue of pyridoxal phosphate. Despite protection of groups capable of interference, the reaction proved impossible, and evidence of elimination of HBr with formation of R—CH=CH—COOH from R—CH2—CHBr—COOH in attempting step 6 was obtained (105). 

Also containing adjacent OH and CHO groups is pyridoxal, and zinc complexes of Schiff bases derived from histidine and pyridoxal have been investigated as models for the reactions of vitamin B6 analogues.343... 

Manousek and Zuman (90) have described a direct polarographic determination of pyridoxal in the presence of pyridoxal 5-phosphate. The simultaneous determination of both compounds is possible only when the concentrations are comparable. The same authors also have reported the polarography of pyridoxine and several analogues in buffered solutions. A 2-electron wave was observed which corresponds to a diffusion-controlled reduction of the activated C-OH bond in position 4. 

Recently, we have purified the potato tuber enzyme,56) modified the enzyme with several types of PLP analogues,17,54) cloned its cDNA,37) and constructed the expression system in E. coli.sg) Fig. 4.2 shows the structures of the reagents used for the modification of the enzyme in comparison with that of the substrate. Although UP2-PL and UP3-PL bound to the enzyme in a 1 1 stoichiometry, five lysyl residues (Lys-263, Lys-329, Lys-367, Lys-409, and Lys-410) were labeled in varying degrees (Table 4.2). Pyridoxal-diphos-... 

Phosphorylase kinase, one of the Ser/Thr-kinases, is oligomeric with the stoichiometry (a/3yS)4.80> The y-subunit of the enzyme is homologous to other protein kinases and possesses protein kinase activity when separated from other subunits.811 Phosphorylase kinase was more effectively inactivated by AP3-PL and AP4-PL than PLP and AP2-PL. Ca2+ and Mg2+, activators for this enzyme, enhanced the degree of inactivation by all the pyridoxal compounds. Inactivation by AP3-PL and AP4-PL was markedly protected by adenylyl, /3,y-imidodiphosphate, a nonhydrolyzable analogue of ATP, and ADP. Because the a- and /3-subunits have regulatory ATP-binding sites and the kinase activity is regulated by these subunits,821 the incorporation of AP3-PL into the y-subunit and... 

Pyridoxal-5-phosphate (PLP) has been shown to be an activator analogue of 3-PGA (7,8). It activates ADPGlc synthetic rates about 5- to 6-fold and can overcome P inhibition as does the activator 3-PGA (7,8). Reductive phosphopyridoxylation of the spinach leaf enzyme with labeled PLP gives incorporation into both subunits in equimolar amounts (7,9). The PLP modified enzyme is less dependent on the presence of activator (3-PGA) and is more resistant to inhibition by the allosteric inhibitor, P (7-9). The activator,... 

Snell, E. E. (1970). Analogues of pyridoxal or pyridoxal phosphate Relation of structure to binding with apoenzymes and to catalytic activity. Vit. Horm. 28, 265-290. 

PIH (pyridoxal isonicotinoylhydrazone) is an orally effective iron CHELATING AGENT. It inhibits lipid peroxidation, and analogues are potential antiproliferative agents, pikstoprofsn [inn] is a member of the propionic acid series, and is a cyclooxygenase inhibitor with nsaid... 

Pyridoxal-5 phosphate (P-5 -P) and its amino analogue, pyridoxamine-5 -phosphate, function as coenzymes in the amino-transfer reactions. The P-5 -P is bound to the apoen-zyme and serves as a true prosthetic group. The P-5 -P bound to the apoenzyme accepts the amino group from the first substrate, aspartate or alanine, to form enzyme-bound pyridoxamine-5 -phosphate and the first reaction product, oxaloacetate or pyruvate, respectively. The coenzyme in amino form then transfers its amino group to the second substrate, 2-oxoglutarate, to form the second product, glutamate. P-5 -P is thus regenerated. 

Stirtan, W.G.. and Withers, S.G., Phosphonate and a-fluorophosphonate analogue of the ionization state of pyridoxal 5 -phosphate (PLP) in glycogen phosphorylase. Biochemistry, 35, 15057, 1996. 

Phosphonylation of a -3-(9-isopropylidene-a -pyridoxyl chloride via a Michaelis-Becker reaction, followed by deprotection with 1 M HCl and oxidation of the resulting primary alcohol with MnOj, produces diethyl (4-fonnyl-3-hydroxy-2-methyl-5-pyridyl)methylphosphonate (Scheme 5.38), an analogue of pyridoxal 5 -phosphate whose 5-position side chain has been replaced by a phospho-nomethyl group. The alcohol oxidation step can be accomplished with a wide range of reagents, such as activated MnOj in CHCI3 at room temperature (53%), PCC in CH2CI2 (83-86%), or the Swem reaction (>95%). ... 

The vinylic and acetylenic analogues of pyridoxal 5 -phosphatc are known. The former can be prepared as a cis-trans mixture by Peterson reaction between a ,3-O-isopropylideneisopyridoxal and diethyl l-lithio-l-(trimethylsilyl)methylphosphonate. Isolation of the cis derivative and subsequent deprotection of the alcohol followed by oxidation with MnO2 in ("HCl, leads to the diethyl... 

An early report suggested that suramin can block the nucleotide-dependent calcium pump of rabbit skeletal sarcoplasmic reticulum by inhibition of the calcium uptake and the ATTase activity [51]. These results have been confirmed by Emmik et al. [52]. Baumert and Heider [53] found that pyridoxal-5-phosphate and a series of its analogues (for chemical structure. 

Inhibitory potency (mean PIC50 values) of pyridoxal-5-phosphate and some of its analogues at P2X"Purinoceptors in rabbit isolated vas deferens ... 

These results show that the phosphate and aldehyde moieties of pyridoxal-5-phosphate and its analogues are required for antagonist activity at P2X Punnoceptors in rabbit vas deferens. Among this series of compounds, PPADS was found to be the most interesting P2-antagonist, and it was therefore the subject of a more detailed pharmacological investigation. 

There is little motion of the protein, the main movement being closure of a loop over the active site after binding phosphate and substrate analogue. There are indications that when an acceptor maltooligosaccharide and glucose-1-phosphate are both bound, the phosphate is forced down and in an unfavourable torsional angle however there is no indication of any direct covalent interaction between the nucleophilic phosphate and the phosphate attached to the pyridoxal moiety, which had been proposed on the basis on NMR studies on glycogen phosphorylase. There is also no indication of any covalent intermediate. Structurally, the S i mechanism is plausible whereas the doubledisplacement mechanism would create difficulties. 

Schnackerz,K.D.,Tai, C.H., Potsch, R.K., and Cook, P.F. (1999) Substitution of pyridoxal 5 -phosphate in D-serine dehydratase from Escherichia coli by cofactor analogues pro videsinformati on oncofactor binding and catalysis. J. Biol. Chem. 274, 36935-36943. 

Canaline is the product of the hydrolytic cleavage of canavanine with the simultaneous formation of urea. Canaline is an ornithine analogue which also shows neurotoxicity in the adult sexta where it adversely affects central nervous system functions (jj ). It also is a potent inhibitor of vitamin B -containing enzymes (20-22). It forms a stable Schiff base with the pyridoxal phosphate moiety of the enzyme and drastically curtails enzymatic activity. Pyridoxal phosphate-containing enzymes are vital to insects because they function in many essential transamination and decarboxylation reactions. Ornithine is an important metabolic precursor for insect production of glutamic acid and proline (23). 

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