L-PIPECOLIC ACID IS OXIDIZED TO α-AMINOADIPIC ACID IN THE PEROXISOME OF MAN AND MONKEY

L-Pipecolic acid (PIP) accumulation is found in Zellweger syndrome (ZS) and other diseases where the structure or function of peroxisomes is defective. Since there is no primate model for PIP metabolism, we compared the pathway in the cynomologus monkey to that in man. Monkey kidney cortices and livers were homogenized and crudely fractionated by differential centrifugation. After incubation with L-[2, 3, 4, 5, 6-3H]PIP, reaction products were separated by thin layer chromatography and on the amino acid analyser. The only radioactive product comigrated with authentic α-aminoadipic acid (AAA) in all systems employed. PIP oxidation was highest in the light mitochondrial (L) fraction, as was activity of catalase, a peroxisomal marker enzyme. After further separation on a Percoll gradient, PIP oxidation again paralleled catalase activity in both liver and kidney. In purified monkey peroxisomes, the activity was membrane associated and could be released by 100 mM KCI. Structural analogs of PIP, such as L-proline, nipecotic acid, piperidine, and cis-2, 4-dicarboxypiperidine, were not inhibitory. In fresh human liver fractionated on a Percoll gradient, PIP oxidation also paralleled catalase activity. Activity was only 6% of control in liver homogenate from a ZS patient (courtesy of Hugo and Ann Moser, Baltimore). The association of the activity with the membrane may explain why PIP metabolism is impaired in disorders where peroxisomal membrane assembly or biogenesis is defective.