841 L-PIPECOLIC ACID (PIP) CATABOLISM IN THE RABBIT: A MODEL FOR PIP METABOLISM IN MAN

Elevated circulating levels of PIP, a putative neurotransmitter, are found in Zellweger syndrome (ZS) and hyperpipecolic acidemia (HPA). As these elevations and the mammalian PIP degradation pathway are poorly understood, we studied L-PIP degradation to α-aminoadipic acid (AAA) in the rabbit. Tissue homogenates converted pure L-[2,3,4,5,6-3H]PIP to 3H-AAA in both rabbit liver and kidney (13.9±9.8 and 34.1±15 pmols/mg prot/hr). Addition of FAD, NAD, and NADP did not raise AAA production and no 3H-AAA was formed in brain homogenates. 3H-AAA identity was confirmed by coelution and re-elution with cold AAA on two paper and one thin layer chromatographic systems. Kidney cortex mitochondria (KCM) formed 3H-AAA from 3H-PIP 14-fold better than tissue homogenates (485±354 pmol/mg prot/hr) and converted 1-2% of the 3H-PIP to 3H-AAA. Addition of 50mM glutamate, a trans-aminase inhibitor, and 1.4mM cold AAA increased AAA recovery 2.7 and 2.8 fold, respectively. Glutamate and cold AAA lowered 3H release from 3H-PIP 45 to 50%, confirming the blockade of 3H-AAA degradation by these compounds. Thus, KCM degrade L-PIP to AAA; the apparent mitochondrial location of this pathway is consistent with its location on the electron transport particle of P. putida, although we cannot totally exclude peroxisomal involvement in mammalian PIP degradation. Further studies on PIP metabolism in rabbit KCM and peroxisomes and in ZS and HPA tissues and fibroblasts are in progress.