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Synthetic Polypeptide Metabolism

I. The Metabolic Fate of Enantiomorphic Polymers

From the Laboratory of Chemical Pathology, Department of Pathology, Harvard Medical School, Boston, Massachusetts, and the Medical Unit, St. Mary's Hospital, London, England

Abstract

A polypeptide composed entirely of D-amino acids, poly D-Glu⁵⁵D-Lys³⁹D-Tyr⁶, can be metabolized by rabbits and elicit antibody formation. The metabolism of the D-polymer implies the existence of D-proteases and D-peptidases in the rabbit which are apparently not induced by injection of the polymer, but rather are constitutive enzymes. The serum elimination patterns are the same for both the D-polymer and its L-isomer: less than 1% remains in the serum after 3 to 4 days and this does not depend upon the amount of polymer injected (up to 60 mg) or the method of iodination.

The amount of L-polymer degraded is independent of the dose up to 60 mg and it is completely degraded in 3 to 4 days. In contrast to this, the amount of the D-polymer degraded is dose dependent and only 25 to 30% of the injected polymer is degraded over 15 to 20 days. In addition, the previous injection of one isomer does not affect the subsequent metabolism of the other isomer. The differences in the amounts of each polymer degraded and the independence of their degradation suggest the existence of different pathways for the metabolism for the D- and L-polymers, at least at some crucial stage.

A large amount of the D-polymer is retained in the animal, with the bulk of it (32%) being in the kidney, less (6%) in the liver, and only a small amount (less than 1%) in the spleen. On the other hand, less than 1% of the L-polymer is retained in the animal and it is all in the liver.

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