TAILIEUCHUNG - Báo cáo khoa học: Role of Tyr84 in controlling the reactivity of Cys34 of human albumin

Cys34 in domain I of the three-domain serum protein albumin is the bind-ing site for a wide variety of biologically and clinically important small molecules, provides antioxidant activity, and constitutes the largest portion of free thiol in blood. Analysis of X-ray structures of albumin reveals that the loop containing Tyr84 occurs in multiple conformations. In structures where the loop is well defined, there appears to be an H-bond between the OH of Tyr84 and the sulfur of Cys34. We show that the reaction of 5,5¢-di-thiobis(2-nitrobenzoic acid) (DTNB) with Tyr84Phe mutant albumin is approximately four times faster than with the wild-type protein between pH 6 and pH 8 | ềFEBS Journal Role of Tyr84 in controlling the reactivity of Cys34 of human albumin Alan J. Stewart1 Claudia A. Blindauer1 Stephen Berezenko2 Darrell Sleep2 David Tooth2 and Peter J. Sadler1 1 Schoolof Chemistry University of Edinburgh Edinburgh UK 2 Delta Biotechnology Ltd Nottingham UK Keywords Cys34 disulfide interchange human albumin NMR thiol Correspondence P. J. Sadler Schoolof Chemistry University of Edinburgh West Mains Road Edinburgh EH9 3JJ UK Fax 44 131650 6453 Tel 44 131650 4729 E-mail Received 21 September 2004 revised 5 November 2004 accepted 10 November 2004 doi Human albumin kDa a amino acids is the most abundant protein in blood plasma typically present at concentrations of w mM 1 . It consists of three structurally homologous largely helical 67 domains I II and III each consisting of two subdomains A and B 2-4 . Like other mammalian albumins human albumin contains 17 disulfide bridges and a free thiol at Cys34 which provides the largest fraction of free thiol in blood serum. Cys34 is completely conserved within mammalian albumins. In plasma about 30 of the Cys34 thiol is blocked by disulfide bond formation with cysteine homocysteine or glutathione. Moreover preparations of albumin usually contain 5-10 of dimeric species with Cys34 being a possible site of dimerization 1 . Thus the state of Cys34 is an important origin for heterogeneity in albumin. There has been much interest in the Cys34 site because not only does it act Cys34 in domain I of the three-domain serum protein albumin is the binding site for a wide variety of biologically and clinically important small molecules provides antioxidant activity and constitutes the largest portion of free thiol in blood. Analysis of X-ray structures of albumin reveals that the loop containing Tyr84 occurs in multiple conformations. In structures where the loop is well defined there appears to be an H-bond between the OH of Tyr84 and the sulfur

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