Activation of Escherichia coli UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase by Fe2+ yields a more efficient enzyme with altered ligand affinity.

Biochemistry
Marcy HernickCarol A Fierke

Abstract

The metal-dependent deacetylase UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) catalyzes the first committed step in lipid A biosynthesis, the hydrolysis of UDP-3-O-myristoyl-N-acetylglucosamine to form UDP-3-O-myristoylglucosamine and acetate. Consequently, LpxC is a target for the development of antibiotics, nearly all of which coordinate the active site metal ion. Here we examine the ability of Fe(2+) to serve as a cofactor for wild-type Escherichia coli LpxC and a mutant enzyme (EcC63A), in which one of the ligands for the inhibitory metal binding site has been removed. LpxC exhibits higher activity (6-8-fold) with a single bound Fe(2+) as the cofactor compared to Zn(2+)-LpxC; both metalloenzymes have a bell-shaped dependence on pH with similar pK(a) values, indicating that at least two ionizations are important for maximal activity. X-ray absorption spectroscopy experiments suggest that the catalytic metal ion bound to Fe(2+)-EcLpxC is five-coordinate, suggesting that catalytic activity may correlate with coordination number. Furthermore, the ligand affinity of Fe(2+)-LpxC compared to the Zn(2+) enzyme is altered by up to 6-fold. In contrast to Zn(2+)-LpxC, the activity of Fe(2+)-LpxC is redox-sens...Continue Reading

References

Nov 8, 1996·Science·H R OnishiC R Raetz
Dec 31, 1997·Biochemistry·M K ChanD Pei
May 20, 1998·Trends in Microbiology·T J WyckoffJ E Jackman
Aug 26, 1998·The Journal of Biological Chemistry·P T Rajagopalan, D Pei
Dec 10, 1998·Nature Structural Biology·A BeckerA F Wagner
Jun 29, 2000·Annual Review of Biochemistry·D W Christianson, J D Cox
Mar 19, 2002·Emerging Infectious Diseases·Lisa D RotzJames M Hughes
Jun 5, 2002·Annual Review of Biochemistry·Christian R H Raetz, Chris Whitfield
Mar 7, 2003·Journal of Inorganic Biochemistry·Craig P McClureJames E Penner-Hahn
Apr 23, 2003·Biochemistry·Jinge ZhuDehua Pei
Jun 24, 2003·Proceedings of the National Academy of Sciences of the United States of America·Douglas A WhittingtonDavid W Christianson
Oct 16, 2003·Current Opinion in Pharmacology·Richard J WhiteZhengyu Yuan
Jan 26, 2005·Biochemistry·Amanda L McClerrenJohannes Rudolph
Jun 22, 2005·Journal of Synchrotron Radiation·Tsu-Chien WengJames E Penner-Hahn
Feb 22, 2008·Protein Science : a Publication of the Protein Society·Igor MochalkinSandra Lightle
Feb 28, 2008·The Journal of Physical Chemistry. B·Jesse J Robinet, James W Gauld
Sep 9, 2009·Biochemistry·Pattraranee LimphongMichael W Crowder
Oct 17, 2009·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Pattraranee LimphongMichael W Crowder

❮ Previous
Next ❯

Citations

Mar 24, 2012·Biochemistry·Danielle MillerRobert H White
Aug 7, 2013·Organic & Biomolecular Chemistry·Marius LöppenbergRalph Holl
Feb 2, 2016·Bioorganic & Medicinal Chemistry·Giovanni TangherliniRalph Holl
Feb 13, 2016·European Journal of Medicinal Chemistry·Hannes MüllerRalph Holl
Dec 18, 2014·Protein Science : a Publication of the Protein Society·Byungchul KimCarol A Fierke
Jul 22, 2017·Chemical Reviews·Aditi R DeshpandeDagmar Ringe
Dec 19, 2016·Inorganic Chemistry·Todor Dudev, Valia Nikolova

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Antifungals (ASM)

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.