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The specificity of lysosomal tripeptidyl peptidase‐I determined by its action on angiotensin‐II analogues
Author(s) -
Warburton Michael J,
Bernardini Francesca
Publication year - 2001
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(01)02608-4
Subject(s) - tripeptide , chemistry , biochemistry , angiotensin ii , enzyme , peptide , amino acid , renin–angiotensin system , dipeptidyl peptidase , stereochemistry , biology , receptor , endocrinology , blood pressure
Tripeptidyl peptidase‐I (TPP‐I) is a lysosomal peptidase which cleaves tripeptides from the N‐terminus of peptides. The function of the enzyme is unclear but its importance is demonstrated by the fact that mutations in TPP‐I are responsible for late infantile neuronal ceroid lipofuscinosis, a lethal lysosomal storage disease. As a step towards identifying its natural substrates, we have used a series of synthetic peptides, based on angiotensin‐II, to explore the effects of peptide chain length and the effects of amino acid substitutions at the P 1 and P 1 ′ positions on the rate of catalysis. With the exception of angiotensin‐(1–8) (angiotensin‐II), which is a relatively poor substrate for TPP‐I, the rate of catalysis increases with increasing chain length. K cat / K m values increase 50‐fold between angiotensin‐(1–5) and angiotensin‐(1–14). TPP‐I shows little specificity for the nature of the amino acids in the P 1 and P 1 ′ positions, K cat / K m values varying only 5‐fold for a range of substitutions. However, Pro or Lys in the P 1 position and Pro in the P 1 ′ positions are incompatible with TPP‐I activity. These observations suggest that TPP‐I is a non‐specific, but essential, peptidase involved in the latter stages of lysosomal protein degradation.