Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.4 (trypsin)
 42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genomic blot analysis raised the possibility that uncharacterized tryptase genes reside on chromosome 17 at the complex containing the three genes that encode mouse mast cell protease (mMCP) 6, mMCP-7, and transmembrane tryptase (mTMT). Probing of GenBank's expressed sequence tag data base with these three tryptase cDNAs resulted in the identification of an expressed sequence tag that encodes a portion of a novel mouse serine protease (now designated mouse tryptase 4 (mT4) because it is the fourth member of this family). 5'- and 3'-rapid amplification of cDNA ends approaches were carried out to deduce the nucleotide sequence of the full-length mT4 transcript. This information was then used to clone its approximately 5.0-kilobase pair gene. Chromosome mapping analysis of its gene, sequence analysis of its transcript, and comparative protein structure modeling of its translated product revealed that mT4 is a new member of the chromosome 17 family of mouse tryptases. mT4 is 40-44% identical to mMCP-6, mMCP-7, and mTMT, and this new serine protease has all of the structural features of a functional tryptase. Moreover, mT4 is enzymatically active when expressed in insect cells. Due to its 17-mer hydrophobic domain at its C terminus, mT4 is a membrane-anchored tryptase more analogous to mTMT than the other members of its family. As assessed by RNA blot, reverse transcriptase-polymerase chain reaction, and/or in situ hybridization analysis, mT4 is expressed in interleukin-5-dependent mouse eosinophils, as well as in ovaries and testes. The observation that recombinant mT4 is preferentially retained in the endoplasmic reticulum of transiently transfected COS-7 cells suggests a convertase-like role for this integral membrane serine protease.
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PMID:Tryptase 4, a new member of the chromosome 17 family of mouse serine proteases. 1125 27

The aim of the present research was to characterize the pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel quinazolinone-based dipeptidyl peptidase-4 (DPP-4) inhibitor. Alogliptin potently inhibited human DPP-4 in vitro (mean IC(50), ~ 6.9 nM) and exhibited > 10,000-fold selectivity for DPP-4 over the closely related serine proteases DPP-2, DPP-8, DPP-9, fibroblast activation protein/seprase, prolyl endopeptidase, and tryptase (IC(50) > 100,000 nM). Absolute oral bioavailability of alogliptin in rats, dogs, and monkeys was 45%, 86%, and 72% to 88%, respectively. After a single oral dose of alogliptin, plasma DPP-4 inhibition was observed within 15 min and maximum inhibition was > 90% in rats, dogs, and monkeys; inhibition was sustained for 12 h in rats (43%) and dogs (65%) and 24 h in monkeys (> 80%). From E(max) modeling, 50% inhibition of DPP-4 activity was observed at a mean alogliptin plasma concentration (EC(50)) of 3.4 to 5.6 ng/ml (10.0 to 16.5 nM) in rats, dogs, and monkeys. In Zucker fa/fa rats, a single dose of alogliptin (0.3, 1, 3, and 10 mg/kg) inhibited plasma DPP-4 (91% to 100% at 2 h and 20% to 66% at 24 h), increased plasma GLP-1 (2- to 3-fold increase in AUC(0-20 min)) and increased early-phase insulin secretion (1.5- to 2.6-fold increase in AUC(0-20 min)) and reduced blood glucose excursion (31%-67% decrease in AUC(0-90 min)) after oral glucose challenge. Alogliptin (30 and 100 mg/kg) had no effect on fasting plasma glucose in normoglycemic rats. In summary, these data suggest that alogliptin is a potent and highly selective DPP-4 inhibitor with demonstrated efficacy in Zucker fa/fa rats and potential for once-daily dosing in humans.
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PMID:Pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel inhibitor of dipeptidyl peptidase-4, in rats, dogs, and monkeys. 1853 60