In vivo selection of transplanted hepatocytes by pharmacological inhibition of fumarylacetoacetate hydrolase in wild-type mice.

Genetic fumarylacetoacetate hydrolase (Fah) deficiency is unique in that healthy gene-corrected hepatocytes have a strong growth advantage and can repopulate the diseased liver. Unfortunately, similar positive selection of gene-corrected cells is absent in most inborn errors of liver metabolism and it is difficult to reach the cell replacement index required for therapeutic benefit. Therefore, methods to transiently create a growth advantage for genetically modified hepatocytes in any genetic background would be advantageous.

Ternary complex formation and induced asymmetry in orotate phosphoribosyltransferase.

Orotate phosphoribosyltransferase (OPRTase, EC 2.4.2.

Slow-onset inhibition of fumarylacetoacetate hydrolase by phosphinate mimics of the tetrahedral intermediate: kinetics, crystal structure and pharmacokinetics.

FAH (fumarylacetoacetate hydrolase) catalyses the final step of tyrosine catabolism to produce fumarate and acetoacetate. HT1 (hereditary tyrosinaemia type 1) results from deficiency of this enzyme. Previously, we prepared a partial mimic of the putative tetrahedral intermediate in the reaction catalysed by FAH co-crystallized with the enzyme to reveal details of the mechanism [Bateman, Bhanumoorthy, Witte, McClard, Grompe and Timm (2001) J.

'Irreversible' slow-onset inhibition of orotate phosphoribosyltransferase by an amidrazone phosphate transition-state mimic.

A mimic of the putative transition-state intermediate has been synthesized and found to be a very slow-onset inhibitor of yeast orotate phosphoribosyltransferase. The mechanism of inhibition may involve a rate-determining isomerization of the enzyme to a form receptive to the inhibitor, which then remains tightly bound.

Half-of-sites binding of orotidine 5'-phosphate and alpha-D-5-phosphorylribose 1-diphosphate to orotate phosphoribosyltransferase from Saccharomyces cerevisiae supports a novel variant of the Theorell-Chance mechanism with alternating site catalysis.

A ping-pong bi-bi kinetic mechanism ascribed to yeast orotate phosphoribosyltransferase (OPRTase) [Victor, J., Greenberg, L. B.