The UDP-diacylglucosamine Pyrophosphohydrolase LpxH in Lipid A Biosynthesis Utilizes Mn2+ Cluster for Catalysis

Young, Hayley; Donohue, Matthew P.; Smirnova, Tatyana I.; Smirnov, Alex I.; Zhou, Pei

doi:10.1074/jbc.m113.497636

Cited by 17 publications

(37 citation statements)

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“…As LpxH is most active in the presence of Mn 2+ , and since our previous EPR study has revealed the presence of a di-manganese cluster in LpxH 12 , these two densities were interpreted as manganese ions. Of the two manganese ions, the first ion (Mn1) is coordinated by sidechains of D42, N80, H115 and H196, while the second ion (Mn2) is coordinated by sidechains of D9, H11, and D42, with D42 bridging the di-manganese cluster (Fig.…”

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confidence: 99%

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Structure of the essential Haemophilus influenzae UDP-diacylglucosamine pyrophosphohydrolase LpxH in lipid A biosynthesis

et al. 2016

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In most Gram-negative pathogens, the hydrolysis of UDP-2,3-diacylglucosamine to generate lipid X in lipid A biosynthesis is catalyzed by the membrane-associated enzyme LpxH. We report the crystal structure of LpxH in complex with its product, lipid X, unveiling a unique insertion lid above the conserved architecture of calcineurin-like phosphoesterases. This structure reveals elaborate interactions surrounding lipid X and provides molecular insights into the substrate selectivity, catalysis, and inhibition of LpxH.

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“…2). Substitutions of these residues by alanine (D9A, H11A, D42A, H115A, and H196A) dramatically reduced the specific activity of LpxH by 5000- to 200,000-fold 12 .…”

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Structure of the essential Haemophilus influenzae UDP-diacylglucosamine pyrophosphohydrolase LpxH in lipid A biosynthesis

et al. 2016

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“…Biochemical characterization shows that E. coli LpxH is a member of the calcineurin-like phosphoesterases (CLPs), requires detergent for full activity, and is an essential enzyme [65, 71]. Further studies using the more stable Haemophilus influenzae LpxH ortholog show that LpxH retains full activity in the presence of Mn 2+ , but not other metal ions, and utilizes a di-manganese cluster for catalysis [72]. …”

Section: Lpxh Lpxi and Lpxgmentioning

confidence: 99%

“…5B ). Alanine substitutions of these metal chelating residues significantly reduced the activity of H. influenzae LpxH [72]. The glucosamine-1-phosphate head group shared by lipid X and the LpxH substrate UDP-DAGn is recognized by an elaborate network of active site residues, which enables LpxH to differentiate its substrate UDP-DAGn from an overwhelming amount of competing phospholipids in the bacterial inner membrane ( Fig.…”

Section: Lpxh Lpxi and Lpxgmentioning

confidence: 99%

“…5E ) [65]. H. influenzae LpxH is most active at slightly alkaline pH values and exhibits a sharp decrease in its catalytic activity at acidic pH [72], consistent with the presence of a general base in the active site, most likely a catalytic histidine residue, with the pKa value of ~6.6 [72], though such a pKa value may alternatively reflect a metal bound water molecule.…”

Section: Lpxh Lpxi and Lpxgmentioning

confidence: 99%

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Structure, inhibition, and regulation of essential lipid A enzymes

Zhou

Zhao

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The Raetz pathway of lipid A biosynthesis plays a vital role in the survival and fitness of Gram-negative bacteria. Research efforts in the past three decades have identified individual enzymes of the pathway and have provided a mechanistic understanding of the action and regulation of these enzymes at the molecular level. This article reviews the discovery, biochemical and structural characterization, and regulation of the essential lipid A enzymes, as well as continued efforts to develop novel antibiotics against Gram-negative pathogens by targeting lipid A biosynthesis.

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Development of LpxH Inhibitors Chelating the Active Site Dimanganese Metal Cluster of LpxH

et al. 2023

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Despite the widespread emergence of multidrug‐resistant nosocomial Gram‐negative bacterial infections and the major public health threat it brings, no new class of antibiotics for Gram‐negative pathogens has been approved over the past five decades. Therefore, there is an urgent medical need for developing effective novel antibiotics against multidrug‐resistant Gram‐negative pathogens by targeting previously unexploited pathways in these bacteria. To fulfill this crucial need, we have been investigating a series of sulfonyl piperazine compounds targeting LpxH, a dimanganese‐containing UDP‐2,3‐diacylglucosamine hydrolase in the lipid A biosynthetic pathway, as novel antibiotics against clinically important Gram‐negative pathogens. Inspired by a detailed structural analysis of our previous LpxH inhibitors in complex with K. pneumoniae LpxH (KpLpxH), here we report the development and structural validation of the first‐in‐class sulfonyl piperazine LpxH inhibitors, JH‐LPH‐45 (8) and JH‐LPH‐50 (13), that achieve chelation of the active site dimanganese cluster of KpLpxH. The chelation of the dimanganese cluster significantly improves the potency of JH‐LPH‐45 (8) and JH‐LPH‐50 (13). We expect that further optimization of these proof‐of‐concept dimanganese‐chelating LpxH inhibitors will ultimately lead to the development of more potent LpxH inhibitors for targeting multidrug‐resistant Gram‐negative pathogens.

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The UDP-diacylglucosamine Pyrophosphohydrolase LpxH in Lipid A Biosynthesis Utilizes Mn2+ Cluster for Catalysis

Cited by 17 publications

References 50 publications

Structure of the essential Haemophilus influenzae UDP-diacylglucosamine pyrophosphohydrolase LpxH in lipid A biosynthesis

Structure of the essential Haemophilus influenzae UDP-diacylglucosamine pyrophosphohydrolase LpxH in lipid A biosynthesis

Structure, inhibition, and regulation of essential lipid A enzymes

Development of LpxH Inhibitors Chelating the Active Site Dimanganese Metal Cluster of LpxH

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