NDLI: Mobile loop mutations in an archaeal inositol monophosphatase: Modulating three-metal ion assisted catalysis and lithium inhibition

Content Provider	PubMed Central
Author	Li, Zheng Stieglitz, Kimberly A. Shrout, Anthony L. Wei, Yang Weis, Robert M. Stec, Boguslaw Roberts, Mary F.
Abstract	The inositol monophosphatase (IMPase) enzyme from the hyperthermophilic archaeon Methanocaldococcus jannaschii requires Mg2+ for activity and binds three to four ions tightly in the absence of ligands: K D = 0.8 μM for one ion with a K D of 38 μM for the other Mg2+ ions. However, the enzyme requires 5–10 mM Mg2+ for optimum catalysis, suggesting substrate alters the metal ion affinity. In crystal structures of this archaeal IMPase with products, one of the three metal ions is coordinated by only one protein contact, Asp38. The importance of this and three other acidic residues in a mobile loop that approaches the active site was probed with mutational studies. Only D38A exhibited an increased kinetic K D for Mg2+; D26A, E39A, and E41A showed no significant change in the Mg2+ requirement for optimal activity. D38A also showed an increased K m, but little effect on k cat. This behavior is consistent with this side chain coordinating the third metal ion in the substrate complex, but with sufficient flexibility in the loop such that other acidic residues could position the Mg2+ in the active site in the absence of Asp38. While lithium ion inhibition of the archaeal IMPase is very poor (IC50∼250 mM), the D38A enzyme has a dramatically enhanced sensitivity to Li+ with an IC50 of 12 mM. These results constitute additional evidence for three metal ion assisted catalysis with substrate and product binding reducing affinity of the third necessary metal ion. They also suggest a specific mode of action for lithium inhibition in the IMPase superfamily.
Related Links	http://dx.doi.org/10.1002/pro.315
Ending Page	318
Page Count	10
Starting Page	309
File Format	PDF
ISSN	09618368
e-ISSN	1469896X
Journal	Protein Science : A Publication of the Protein Society
Issue Number	2
Volume Number	19
Language	English
Publisher	Wiley Subscription Services, Inc., A Wiley Company
Publisher Date	2010-02-01
Access Restriction	Open
Rights Holder	Wiley Subscription Services, Inc., A Wiley Company
Subject Keyword	Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine Molecular Biology Biochemistry

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Mobile loop mutations in an archaeal inositol monophosphatase: Modulating three-metal ion assisted catalysis and lithium inhibition

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