Tripeptidyl aminopeptidase in the extralysosomal fraction of rat liver.

Bålöw, R M; Ragnarsson, Ulf; Zetterqvist, Örjan

doi:10.1016/s0021-9258(17)44273-6

Cited by 69 publications

(2 citation statements)

References 27 publications

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“…The inhibitors wherein R 3 = CH 3 CH 2 have an inherent stability, since the unnatural amino acid Abu (α-aminobutyric acid) is much less susceptible to proteolysis by the natural proteases; furthermore, proline at P 2 is itself resistant to TPP II, since this enzyme cannot cleave before or after proline residues. − …”

Section: Resultsmentioning

confidence: 99%

“…A simple peptidase was shown 10a to effect both cleavages of CCK-8 and to correspond to tripeptidyl peptidase II (TPP II; EC 3.4.14.10). This is a subtilisin-like serine peptidase that was initially purified from cytosolic extracts of rat liver and human erythrocytes, but it is found in a variety of tissues . It is an unusually large exopeptidase (subunits have a relative molecular mass 138 000) that at neutral pH removes tripeptide from the free N -terminus of longer peptides…”

Section: Introductionmentioning

confidence: 99%

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Inhibitors of Tripeptidyl Peptidase II. 3. Derivation of Butabindide by Successive Structure Optimizations Leading to a Potential General Approach to Designing Exopeptidase Inhibitors

et al. 2005

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The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase that has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO3H)-Met-OH + Gly-Trp-Met-Asp-Phe-NH2. Starting from Val-Pro-NHBu, a dipeptide of submicromolar affinity that had previously been generated to serve as a lead, successive optimization at P3, P1, and then P2 gave Abu-Pro-NHBu (18, Ki = 80 nM). Further transformation (by making a benzologue) gave the indoline analogue, butabindide (33) as a reversible inhibitor having nanomolar affinity (Ki = 7 nM). Retrospective analysis suggested the possibility of a general approach to designing exopeptidase inhibitors starting from the structure of the first hydrolysis product. Application of this approach to CCK-8 led to Abu-Phe-NHBu (37), but this only had Ki = 9.4 microM. Molecular modeling, to determine the minimum energy conformations and explain the 1000-fold better affinity of butabindide, indicated that 37 cannot access the likely active conformation of butabindide.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%