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Albumin Is A Substrate Of Human Chymase
W. Raymond, S. W. Ruggles, C. Craik, G. Caughey
Published 2003 · Chemistry, Medicine
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Human chymase is a chymotryptic serine peptidase stored and secreted by mast cells. Compared with other chymotryptic enzymes, such as cathepsin G and chymotrypsin, it is much more slowly inhibited by serum serpins. Although chymase hydrolyzes several peptides and proteins in vitro, its target repertoire is limited compared with chymotrypsin because of selective interactions in an extended substrate-binding site. The best-known natural substrate, angiotensin I, is cleaved to generate vasoactive angiotensin II. Selectivity of angiotensin cleavage depends in major part on interactions involving substrate residues on the carboxyl-terminal (P1′–P2′) side of the cleaved bond. To identify new targets based on interactions with residues on the aminoterminal (P4–P1) side of the site of hydrolysis, we profiled substrate preferences of recombinant human chymase using a combinatorial, fluorogenic peptide substrate library. Data base queries using the peptide (Arg-Glu-Thr-Tyr-X) generated from the most preferred amino acid at each subsite identify albumin as the sole, soluble, human extracellular protein containing this sequence. We validate the prediction that this site is chymase-susceptible by showing that chymase hydrolyzes albumin uniquely at the predicted location, with the resulting fragments remaining disulfide-linked. The site of hydrolysis is highly conserved in vertebrate albumins and is near predicted sites of metal cation binding, but nicking by chymase does not alter binding of Cu2+ or Zn2+. A synthetic peptidic inhibitor, diphenyl Nα-benzoxycarbonyl-l-Arg-Glu-Thr-PheP-phosphonate, was designed from the preferred P4–P1 substrate sequence. This inhibitor is highly potent (IC50 3.8 nm) and 2,700- and 1,300-fold selective for chymase over cathepsin G and chymotrypsin, respectively. In summary, these findings reveal albumin to be a substrate for chymase and identify a potentially useful new chymase inhibitor.
This paper references
Protease composition of exocytosed human skin mast cell protease-proteoglycan complexes. Tryptase resides in a complex distinct from chymase and carboxypeptidase.
Sanford M. Goldstein (1992)
Crystal structures of alpha-lytic protease complexes with irreversibly bound phosphonate esters.
R. Bone (1991)
Structure-activity relationship studies of chloromethyl ketone derivatives for selective human chymase inhibitors.
Y. Hayashi (2000)
Crystal structure of phenylmethanesulfonyl fluoride-treated human chymase at 1.9 A.
M. Mcgrath (1997)
Characterization of the Co2+ and Ni2+ binding amino‐acid residues of the N‐terminus of human albumin
D. Bar-Or (2001)
Inhibition of trypsin and thrombin by amino(4-amidinophenyl)methanephosphonate diphenyl ester derivatives: X-ray structures and molecular models.
J. Bertrand (1996)
A closely linked complex of mouse mast cell-specific chymase genes on chromosome 14.
M. Gurish (1993)
Rapid conversion of angiotensin I to angiotensin II by neutrophil and mast cell proteinases.
C. Reilly (1982)
Specificity of human cathepsin G.
J. Polanowska (1998)
Limited proteolysis of Cl‐inhibitor by chymotrypsin‐like proteinases
Oeyvind L. Schoenberger (1989)
Human skin chymotryptic proteinase. Isolation and relation to cathepsin g and rat mast cell proteinase I.
N. Schechter (1983)
Human leukocyte cathepsin G. Subsite mapping with 4-nitroanilides, chemical modification, and effect of possible cofactors.
T. Tanaka (1985)
Highly efficient inhibition of human chymase by alpha(2)-macroglobulin.
M. Walter (1999)
Structure of serum albumin.
D. Carter (1994)
Inactivation of bradykinin and kallidin by cathepsin G and mast cell chymase.
C. Reilly (1985)
Rapid and general profiling of protease specificity by using combinatorial fluorogenic substrate libraries.
J. Harris (2000)
Cleavage of Type I Procollagen by Human Mast Cell Chymase Initiates Collagen Fibril Formation and Generates a Unique Carboxyl-terminal Propeptide*
M. Kofford (1997)
Mammalian chymotrypsin-like enzymes. Comparative reactivities of rat mast cell proteases, human and dog skin chymases, and human cathepsin G with peptide 4-nitroanilide substrates and with peptide chloromethyl ketone and sulfonyl fluoride inhibitors.
J. Powers (1985)
Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart.
H. Urata (1990)
Activation of human interstitial procollagenase through direct cleavage of the Leu83-Thr84 bond by mast cell chymase.
J. Saarinen (1994)
The cDNA Sequence of Human Endothelial Cell Multimerin
C. Hayward (1995)
Chymase cleavage of stem cell factor yields a bioactive, soluble product.
B. Longley (1997)
Structure of human pro-chymase: a model for the activating transition of granule-associated proteases.
K. K. Reiling (2003)
Inhibition of chymotryptic enzymes by alkane phosphonates Compound IC50 ( M) a Chymase Cathepsin G Chymotrypsin
A. Nakano (1997)
Lys40 but not Arg143 influences selectivity of angiotensin conversion by human α-chymase
D. Muilenburg (2002)
Identification of a cathepsin G-like proteinase in the MCTC type of human mast cell.
N. Schechter (1990)
Distinct Multisite Synergistic Interactions Determine Substrate Specificities of Human Chymase and Rat Chymase-1 for Angiotensin II Formation and Degradation*
S. Sanker (1997)
Reaction of human skin chymotrypsin-like proteinase chymase with plasma proteinase inhibitors.
N. Schechter (1989)
On the active site of proteases. 3. Mapping the active site of papain; specific peptide inhibitors of papain.
I. Schechter (1968)
Proteolytic Enzymes (Barrett
G. H. Caughey (1998)
The interaction between human and bovine serum albumin and zinc studied by a competitive spectrophotometry.
E. Ohyoshi (1999)
Sheep mast cell proteinase-1: characterization as a member of a new class of dual-specific ruminant chymases.
A. Pemberton (1997)
Structure, chromosomal assignment, and deduced amino acid sequence of a human gene for mast cell chymase.
G. Caughey (1991)
The human mast cell chymase gene (CMA1): mapping to the cathepsin G/granzyme gene cluster and lineage-restricted expression.
G. Caughey (1993)
Definition of the Extended Substrate Specificity Determinants for β-Tryptases I and II*
J. Harris (2001)
Handbook of proteolytic enzymes
A. Barrett (1998)
Crystal structures of human serum albumin complexed with monounsaturated and polyunsaturated fatty acids.
I. Petitpas (2001)
Inhibitors of human heart chymase based on a peptide library.
M. Bastos (1995)
Selective conversion of big endothelins to tracheal smooth muscle-constricting 31-amino acid-length endothelins by chymase from human mast cells.
A. Nakano (1997)
Angiotensin II generation by mast cell α- and β-chymases
G. Caughey (2000)
Mast Cell α-Chymase Reduces IgE Recognition of Birch Pollen Profilin by Cleaving Antibody-Binding Epitopes1
Matthew B Mellon (2002)
ProMod and Swiss-Model: Internet-based tools for automated comparative protein modelling.
M. Peitsch (1996)
Two types of human mast cells that have distinct neutral protease compositions.
A. A. Irani (1986)
Rapid and specific conversion of precursor interleukin 1 beta (IL-1 beta) to an active IL-1 species by human mast cell chymase
H. Mizutani (1991)
Genes for mast-cell serine protease and their molecular evolution
R. Huang (2004)
Multiple determinants for the high substrate specificity of an angiotensin II-forming chymase from the human heart.
A. Kinoshita (1991)
This paper is referenced by
Human mast cells arise from a common circulating progenitor.
Katariina Maaninka (2013)
Cleavage Specificity of Mast Cell Chymases
M. Andersson (2008)
Extended cleavage specificity of the mast cell chymase from the crab-eating macaque (Macaca fascicularis): an interesting animal model for the analysis of the function of the human mast cell chymase.
M. Thorpe (2012)
This information is current as Lost Efficiency during Primate Evolution Cathepsin G Gained Tryptic Function but How Immune Peptidases Change Specificity :
Wilfred W. Raymond (2010)
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G. Caughey (2004)
Biological Function of Mast Cell Chymase In vitro and in vivo studies: a thorny pathway
E. Chugunova (2004)
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Christine Bolitho (2010)
Biological functions and regulation of serglycin-dependent mast cell proteases
A. Lundequist (2006)
Protease Mediators of Anaphylaxis
G. Caughey (2011)
Biological function of mast cell chymase
E. Chugunova (2004)
A Pulmonary Perspective on GASPIDs: Granule-Associated Serine Peptidases of Immune Defense.
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Mast cell tryptases and chymases in inflammation and host defense
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Atheroinflammatory Properties of LDL and HDL Particles Modified by Human Mast Cell Neutral Proteases
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Haematopoietic Serine Proteases : A Cleavage Specificity Analysis
Michael Thorpe (2014)
Expansion of the mast cell chymase locus over the past 200 million years of mammalian evolution
Maike Gallwitz (2006)
Mast Cells as sentinels: Role of sergly cin
Mast Cell and Neutrophil Peptidases Attack an Inactivation Segment in Hepatocyte Growth Factor to Generate NK4-like Antagonists*
W. Raymond (2006)
Mast cell proteases as pharmacological targets.
G. Caughey (2016)
Tissue factor pathway inhibitor is highly susceptible to chymase‐mediated proteolysis
T. Hamuro (2007)
Chapter 590 – Chymases
G. Caughey (2013)
Screening Combinatorial Peptide Libraries in Protease Inhibitor Drug Discovery
M. Poręba (2018)
Human Mast Cell Chymase Cleaves Pro-IL-18 and Generates a Novel and Biologically Active IL-18 Fragment1
Y. Omoto (2006)
This information is current as for Degradation of Cytokines ResponsibleCells : Endogenous Proteases Are Cytokine Production by Skin-Derived Mast
Wei Zhao (2005)
How Immune Peptidases Change Specificity: Cathepsin G Gained Tryptic Function but Lost Efficiency during Primate Evolution
W. Raymond (2010)
Decrease in chymase activity is associated with increase in IL-6 expression in mast cells in atopic dermatitis.
T. Ilves (2015)
Cytokine Production by Skin-Derived Mast Cells: Endogenous Proteases Are Responsible for Degradation of Cytokines 1
W. Zhao (2005)
Human mast cell neutral proteases generate modified LDL particles with increased proteoglycan binding.
Katariina Maaninka (2018)
α2-Macroglobulin Capture Allows Detection of Mast Cell Chymase in Serum and Creates a Reservoir of Angiotensin II-Generating Activity1
W. Raymond (2009)
Guinea Pig Chymase Is Leucine-specific
G. Caughey (2008)
Mast cell proteases as protective and inflammatory mediators.
G. Caughey (2011)
Extended substrate specificity of opossum chymase--implications for the origin of mast cell chymases.
J. Reimer (2008)
Mast cell chymase degrades fibrinogen and fibrin
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