The proposed work represents the continuation of our studies of renal and blood enzymes that cleave biologically active peptides. Carboxypeptidase N, discovered in this laboratory, cleaves basic C-terminal amino acids of kinins, anaphylatoxins and several plasma proteins. We will establish the amino acid sequence of the high and low molecular weight subunits of the enzyme from the cDNA nucleotide sequence. We will determine the role of the high molecular weight inactive subunit in the hydrolysis of high mol. wt. protein substrates. We will study the distribution of the enzyme outside the liver by determining the mRNA content of various organs. Angiotensin I converting enzyme is also kininase II. Its inhibitors are widely accepted in the treatment of hypertension and congestive heart failure. Although the enzyme has been considered to be a peptidyl dipeptidase cleaving of dipeptides with free COOH group from substrates such as bradykinin, angiotensin I or enkephalins, we recently found that it also hydrolyzes tripeptides from the protected C-terminal end and even the blocked N-terminal end of peptides. The cleavage of peptide hormones at the N-terminal end will be explored further with various biologically active substrates. The angiotensin I coverting enzyme is bound to plasma membranes throughout the body. Attempts will be made to isolate and characterize the hydrophobic anchor peptide which presumably binds the enzyme to the bilayer of cell membranes. Finally, we will characterize and purify a kininase present, presumably in the brush border of the proximal tubules, which is insensitive to inhibitorts of angiotensin I converting enzyme or neutral endopeptidase (enkephalinase) and cleaves peptides such as bradykinin and larger proteins in the kidney.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37HL036473-03
Application #
3486116
Study Section
Cardiovascular and Pulmonary Research B Study Section (CVB)
Project Start
1988-05-01
Project End
1993-04-30
Budget Start
1988-05-01
Budget End
1989-04-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Erdos, Ervin G; Deddish, Peter A (2002) The kinin system: suggestions to broaden some prevailing concepts. Int Immunopharmacol 2:1741-6
Erdos, Ervin G (2002) Kinins, the long march--a personal view. Cardiovasc Res 54:485-91

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