Mj. Warburton et F. Bernardini, The specificity of lysosomal tripeptidyl peptidase-I determined by its action on angiotensin-II analogues, FEBS LETTER, 500(3), 2001, pp. 145-148
Tripeptidyl peptidase-I (TPP-I) is a lysosomal peptidase which cleaves trip
eptides from the N-terminus of peptides, The function of the enzyme is uncl
ear 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 subst
rates, 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 a
cid substitutions at the P-1 and P-1' positions on the rate of catalysis. W
ith the exception of angiotensin-(1-8) (angiotensin-II), which is a relativ
ely poor substrate for TPP-I, the rate of catalysis increases with increasi
ng 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 onl
y 5-fold for a range of substitutions. However, Pro or Lys in the P-1 posit
ion and Pro in the P-1' positions are incompatible with TPP-I activity, The
se observations suggest that TPP-I is a non-specific, but essential, peptid
ase involved in the latter stages of lysosomal protein degradation. (C) 200
1 Federation of European Biochemical Societies, Published by Elsevier Scien
ce B.V. All rights reserved.