Inhibition of Pyridoxal Kinase by Methylxanthines

Abstract

In the presence of saturating concentrations of adenosine triphosphate (ATP) and rate-limiting amounts of pyridoxal, theophylline was found to inhibit sheep brain pyridoxal kinase (EC 2.7.1.35) competitively. The apparent inhibition constant (K(i)) of theophylline for pyridoxal kinase was determined as 8.7 μmol/l. Theophylline concentrations of up to 60 μmol/1 did not affect pyridoxal phosphorylation in the presence of saturating amounts of pyridoxal and rate-limiting concentrations of ATP. Caffeine was less potent to inhibit pyridoxal kinase (K(i) = 45 μmol/l) due to the presence of a methyl group on the 7 position of the xanthine ring structure. Theobromine showed only a weak inhibition of pyridoxal kinase (K(i) = 453 μmol/l). The presence of a hydroxyethyl, hydroxypropyl or dihydroxypropyl group on the N7 position of theophylline completely abolished inhibition of pyridoxal kinase. Enprofylline (3-propylxanthine), a recently described bronchodilator, was also able to inhibit pyridoxal kinase with a K, of 256 μmol/l.

Human Pyridoxal Kinase

“…The pyridoxal kinase activity of these cells was increased by more than 100-fold following transfection with the PKH cDNA. The recombinant enzyme displayed a K m value for pyridoxal (3.3 M) that is within the range of values reported for mammalian preparations of pyridoxal kinase (3-50 M) (16,17,22). Competitive inhibition by 4-deoxypyridoxine and a requirement for ATP and divalent cations are properties of PKH that are also consistent with mammalian pyridoxal kinases (16,17).…”

Inhibition of human pyridoxal kinase by 2-acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI)

“…Interestingly, human pyridoxal kinase is inhibited by a range of substances of natural and synthetic origin, especially by small heterocyclic compounds, e.g. ginkgotoxin or theophylline [12][13][14][15] . Hence, inhibition of pyridoxal kinase by THI does not appear unlikely and we considered a detailed investigation worthwhile.…”

“…Human pyridoxal kinase has been shown to be inhibited by a range of substances of natural and synthetic origin, especially by small heterocyclic compounds. Some well-known drugs inhibit human pyridoxal kinase, causing a number of unwanted neurotoxic side effects [12][13][14][15] . Some reports, however, question that the pyridoxal kinase inhibiting properties of class III caramel colourings actually originate from THI 16 .…”

The oxidant stress of hyperhomocyst(e)inemia.

“…These investigators examined the effects of a selective deficiency of pyridoxal 5 Ј -phosphate on plasma homocyst(e)ine levels after an oral methionine challenge. This deficiency occurred in asthmatic individuals chronically treated with theophylline, a competitive inhibitor of pyridoxal kinase (13). They observed in these individuals with normal folate and vitamin B-12 concentrations that theophylline treatment led to significantly higher plasma homocyst(e)ine and serum cystathionine concentrations after methionine challenge compared with controls.…”