Disruption of histidine catabolism in NEUT2 mice.
Homozygous NEUT2 mice lack cytosolic 10-formyltetrahydrofolate dehydrogenase (FDH; Champion et al. (1994) Proc. Natl. Acad. Sci. USA 91, 11,338-11,342) and as a consequence should be unable to oxidize carbon 2 of l-histidine to CO2 via 10-formyltetrahydrofolate in liver cytosol. There was essentially no oxidation of l-[2-14C]histidine to 14CO2 in homozygous NEUT2 mice, but 52% of the [2-14C]l-histidine dose was recovered in the urine within 24 h. Analysis of urine samples for [14C]formiminoglutamate, the expected excretion product, was negative; however, [14C]urocanic acid was detected. Investigation of histidine catabolism via the folate-dependent deamination pathway revealed no detectable urocanase activity in homozygous NEUT2 mice, while heterozygous NEUT2 mice had 50% urocanase activity compared to normal mice. Histidase and formiminotransferase-cyclodeaminase, also on the histidine deamination pathway, had similar specific activities in normal and NEUT2 mice. Histidine-pyruvate aminotransferase, the first enzyme of the alternate histidine transamination catabolic pathway did not appear to be affected by the loss of urocanase. Based on the excretion of urocanic acid it is estimated that NEUT2 mice catabolize approximately 40 micromol/day via the deamination pathway. The loss of urocanase activity in homozygous NEUT2 mice may allow these mice to survive the disruption in folate metabolism by sparing the liver cytosolic tetrahydrofolate pool.
Cook
R J
RJ
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. cookrj@ctrvax.vanderbilt.edu
D000818:Animals; D003600:Cytosol / Q000378:metabolism; D005838:Genotype; D018698:Glutamic Acid / Q000652:urine; D006579:Heterozygote; D006639:Histidine / Q000378:metabolism*; D006720:Homozygote; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008956:Models, Chemical; D010100:Oxygen / Q000378:metabolism; D000637:Transaminases / Q000378:metabolism; D014560:Urocanic Acid / Q000652:urine
D018698:Glutamic Acid; D006639:Histidine; D000637:Transaminases; C021357:histidine aminotransferase; D014560:Urocanic Acid; D010100:Oxygen