ArticleThe Journal of biological chemistry2008
Guinea pig chymase is leucine-specific: a novel example of functional plasticity in the chymase/granzyme family of serine peptidases.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 24 citations in OpenAlex.
- The Evolutionary History of theInternational journal of molecular sciences · 2021Review
- Extended cleavage specificities of two mast cell chymase-related proteases and one granzyme B-like protease from the platypus, a monotreme.International journal of molecular sciences · 2020Article
- Extended Cleavage Specificities of Rabbit and Guinea Pig Mast Cell Chymases: Two Highly Specific Leu-Ases.International journal of molecular sciences · 2019Article
- Estrogen modulates the differential expression of cardiac myocyte chymase isoforms and diastolic function.Molecular and cellular biochemistry · 2019Article
- Article
- Mast cell proteases as pharmacological targets.European journal of pharmacology · 2016Review
- Article
- Mutational tail loss is an evolutionary mechanism for liberating marapsins and other type I serine proteases from transmembrane anchors.The Journal of biological chemistry · 2013Article
- Mutations in Arg143 and Lys192 of the Human Mast Cell Chymase Markedly Affect the Activity of Five Potent Human Chymase Inhibitors.PloS one · 2013Article
- Remodeling of intrinsic cardiac neurons: effects of β-adrenergic receptor blockade in guinea pig models of chronic heart disease.American journal of physiology. Regulatory, integrative and comparative physiology · 2012Article
- How immune peptidases change specificity: cathepsin G gained tryptic function but lost efficiency during primate evolution.Journal of immunology (Baltimore, Md. : 1950) · 2010Article
- Mast cell peptidases: chameleons of innate immunity and host defense.American journal of respiratory cell and molecular biology · 2010Review
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
Abstract
To explore guinea pigs as models of chymase biology, we cloned and expressed the guinea pig ortholog of human chymase. In contrast to rats and mice, guinea pigs appear to express just one chymase, which belongs to the alpha clade, like primate chymases and mouse mast cell protease-5. The guinea pig enzyme autolyzes at Leu residues in the loop where human chymase autolyzes at Phe. In addition, guinea pig alpha-chymase selects P1 Leu in a combinatorial peptide library and cleaves Ala-Ala-Pro-Leu-4-nitroanilide but has negligible activity toward substrates with P1 Phe and does not cleave angiotensin I. This contrasts with human chymase, which cleaves after Phe or Tyr, prefers P1 Phe in peptidyl 4-nitroanilides, and avidly hydrolyzes angiotensin I at Phe8 to generate bioactive angiotensin II. The guinea pig enzyme also is inactivated more effectively by alpha1-antichymotrypsin, which features P1 Leu in the reactive loop. Unlike mouse, rat, and hamster alpha-chymases, guinea pig chymase lacks elastase-like preference for P1 Val or Ala. Partially humanized A216G guinea pig chymase acquires human-like P1 Phe- and angiotensin-cleaving capacity. Molecular models suggest that the wild type active site is crowded by the Ala216 side chain, which potentially blocks access by bulky P1 aromatic residues. On the other hand, the guinea pig pocket is deeper than in Val-selective chymases, explaining the preference for the longer aliphatic side chain of Leu. These findings are evidence that chymase-like peptidase specificity is sensitive to small changes in structure and provide the first example of a vertebrate Leu-selective peptidase.
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