Purification, substrate specificity, and classification of tripeptidyl peptidase II.

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

doi:10.1016/s0021-9258(17)35951-3

Cited by 97 publications

(3 citation statements)

References 24 publications

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“…Tripeptidyl peptidase II (TPPII) is a well‐conserved and large exopeptidase with an uncommon structure. The TPPII protease domain, located at the amino terminus, has high similarity to other proteases; TPPII also has a conserved, unique and unusually long carboxy‐terminal extension of unknown function (Balow et al , 1986; Tomkinson, 1994). TPPII is expressed in many cells and has various intracellular proteolytic actions including peptide processing for antigen presentation, Shigella ‐induced macrophage apoptosis and protein turnover (Geier et al , 1999; Hilbi et al , 2000; Seifert et al , 2003).…”

Section: Introductionmentioning

confidence: 99%

Tripeptidyl peptidase II promotes fat formation in a conserved fashion

McKay¹,

McKay²,

Suh³

et al. 2007

EMBO Reports

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Tripeptidyl peptidase II (TPPII) is a multifunctional and evolutionarily conserved protease. In the mammalian hypothalamus, TPPII has a proposed anti-satiety role affected by degradation of the satiety hormone cholecystokinin 8. Here, we show that TPPII also regulates the metabolic homoeostasis of Caenorhabditis elegans; TPPII RNA interference (RNAi) decreases worm fat stores. However, this occurs independently of feeding behaviour and seems to be a function within fat-storing tissues. In mammalian cell culture, TPPII stimulates adipogenesis and TPPII RNAi blocks adipogenesis. The pro-adipogenic action of TPPII seems to be independent of protease function, as catalytically inactive TPPII also increases adipogenesis. Mice that were homozygous for an insertion in the Tpp2 locus were embryonic lethal. However, Tpp2 heterozygous mutants were lean compared with wild-type littermates, although food intake was normal. These findings indicate that TPPII has central and peripheral roles in regulating metabolism and that TPPII actions in fat-storing tissues might be an ancient function carried out in a protease-independent manner.

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Section: Introductionmentioning

confidence: 99%

Tripeptidyl peptidase II promotes fat formation in a conserved fashion

McKay¹,

McKay²,

Suh³

et al. 2007

EMBO Reports

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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%

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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The Ubiquitin–Proteasome System in Epstein‐Barr Virus Infection and Oncogenesis

Masucci

2007

Protein Degradation Series

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Purification, substrate specificity, and classification of tripeptidyl peptidase II.

Cited by 97 publications

References 24 publications

Tripeptidyl peptidase II promotes fat formation in a conserved fashion

Tripeptidyl peptidase II promotes fat formation in a conserved fashion

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

The Ubiquitin–Proteasome System in Epstein‐Barr Virus Infection and Oncogenesis

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