alexa Clustered Conserved Cysteines in Hyaluronan Synthase Mediate Cooperative Activation by Mg2+ Ions and Severe Inhibitory Effects of Divalent Cations | OMICS International | Abstract
ISSN: 2153-0637

Journal of Glycomics & Lipidomics
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Special Issue Article

Clustered Conserved Cysteines in Hyaluronan Synthase Mediate Cooperative Activation by Mg2+ Ions and Severe Inhibitory Effects of Divalent Cations

Valarie L. Tlapak-Simmons, Andria P. Medina, Bruce A. Baggenstoss, Long Nguyen, Christina A. Baron and Paul H. Weigel*

Department of Biochemistry & Molecular Biology, The Oklahoma Center for Medical Glycobiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA

*Corresponding Author:
Paul H. Weigel
Department of Biochemistry & Molecular Biology
The Oklahoma Center for Medical Glycobiology
University of Oklahoma Health Sciences Center
Oklahoma City, OK 73190, USA
Tel: 405-271-1288
Fax: 405-271-3092
E-mail: [email protected]

Received date: August 19, 2011; Accepted date: November 11, 2011; Published date: November 15, 2011

Citation: Tlapak-Simmons VL, Medina AP, Baggenstoss BA, Nguyen L, Baron CA, et al. (2011) Clustered Conserved Cysteines in Hyaluronan Synthase Mediate Cooperative Activation by Mg2+ Ions and Severe Inhibitory Effects of Divalent Cations. J Glycom Lipidom S1:001. doi: 10.4172/2153-0637.S1-001

Copyright: © 2011 Tlapak-Simmons VL, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Hyaluronan synthase (HAS) uses UDP-GlcUA and UDP-GlcNAc to make hyaluronan (HA). Streptococcus equisimilis HAS (SeHAS) contains four conserved cysteines clustered near the membrane, and requires phospholipids and Mg2+ for activity. Activity of membrane-bound or purified enzyme displayed a sigmoidal saturation profile for Mg2+ with a Hill coefficient of 2. To assess if Cys residues are important for cooperativity we examined the Mg2+ dependence of mutants with various combinations of Cys-to-Ala mutations. All Cys-mutants lost the cooperative response to Mg2+. In the presence of Mg2+, other divalent cations inhibited SeHAS with different potencies (Cu2+~Zn2+ >Co2+ >Ni2+ >Mn2+ >Ba2+ Sr2+ Ca2+). Some divalent metal ions likely inhibit by displacement of Mg2+-UDP-Sugar complexes (e.g. Ca2+, Sr2+ and Ba2+ had apparent Ki values of 2-5 mM). In contrast, Zn2+ and Cu2+ inhibited more potently (apparent Ki ≤ 0.2 mM). Inhibition of Cys-null SeHAS by Cu2+, but not Zn2+, was greatly attenuated compared to wildtype. Double and triple Cys-mutants showed differing sensitivities to Zn2+ or Cu2+. Wildtype SeHAS allowed to make HA prior to exposure to Zn2+ or Cu2+ was protected from inhibition, indicating that access of metal ions to sensitive functional groups was hindered in processively acting HA●HAS complexes. We conclude that clustered Cys residues mediate cooperative interactions with Mg2+ and that transition metal ions inhibit SeHAS very potently by interacting with one or more of these –SH groups.

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