Fetuin-A and cystatin C are endogenous inhibitors of human meprin metalloproteases

Hedrich, Jana; Lottaz, Daniel; Meyer, Katharina; Yiallouros, Irene; Jahnen-Dechent, Willi; Stöcker, Walter; Becker-Pauly, Christoph (2010). Fetuin-A and cystatin C are endogenous inhibitors of human meprin metalloproteases. Biochemistry, 49(39), pp. 8599-607. Washington, D.C.: American Chemical Society 10.1021/bi1004238

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Meprin and , zinc metalloproteinases, play significant roles in inflammation, including inflammatory bowel disease (IBD), possibly by activating cytokines, like interleukin 1 , interleukin 18, or tumor growth factor . Although a number of potential activators for meprins are known, no endogenous inhibitors have been identified. In this work, we analyzed the inhibitory potential of human plasma and identified bovine fetuin-A as an endogenous meprin inhibitor with a K(i) (inhibition constant) of 4.2 × 10(-5) M for meprin and a K(i) of 1.1 × 10(-6) M meprin . This correlated with data obtained for a fetuin-A homologue from carp (nephrosin inhibitor) that revealed a potent meprin and inhibition (residual activities of 27 and 22%, respectively) at a carp fetuin concentration of 1.5 × 10(-6) M. Human fetuin-A is a negative acute phase protein involved in inflammatory diseases, thus being a potential physiological regulator of meprin activity. We report kinetic studies of fetuin-A with the proteolytic enzymes astacin, LAST, LAST_MAM, trypsin, and chymotrypsin, indeed demonstrating that fetuin-A is a broad-range protease inhibitor. Fetuin-A inhibition of meprin activity was 40 times weaker than that of meprin activity. Therefore, we tested cystatin C, a protein structurally closely related to fetuin-A. Indeed, cystatin C was an inhibitor for human meprin (K(i) = 8.5 × 10(-6) M) but, interestingly, not for meprin . Thus, the identification of fetuin-A and cystatin C as endogenous proteolytic regulators of meprin activity broadens our understanding of the proteolytic network in plasma.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology and Immunology
UniBE Contributor:	Lottaz, Daniel
ISSN:	0006-2960
Publisher:	American Chemical Society
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:10
Last Modified:	05 Dec 2022 14:01
Publisher DOI:	10.1021/bi1004238
PubMed ID:	20806899
Web of Science ID:	000282144400016
URI:	https://boris.unibe.ch/id/eprint/1677 (FactScience: 203550)