Structural Basis of Lipid Binding for the Membrane-embedded Tetraacyldisaccharide-1-phosphate 4′-Kinase LpxK

Emptage, R.P.; Tonthat, Nam K.; York, John D.; Schumacher, Maria A.; Zhou, Pei

doi:10.1074/jbc.m114.589986

Cited by 8 publications

(16 citation statements)

References 38 publications

(51 reference statements)

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“…Phosphorylation may occur with the lipid still anchored in a membrane in some instances [35]. However, for SK1 the complete enclosure of Sph within the CTD suggests a full lipid extraction-encapsulation action.…”

Section: Lipid Substrate Accessmentioning

confidence: 99%

Sphingosine Kinases: Emerging Structure–Function Insights

Adams

Pyne

2016

Trends in Biochemical Sciences

118

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Sphingosine kinases (SK1 and SK2) catalyse the conversion of sphingosine into sphingosine 1-phosphate and control fundamental cellular processes, including cell survival, proliferation, differentiation, migration, and immune function. In this review, we highlight recent breakthroughs in the structural and functional characterisation of SK1 and these are contextualised by analysis of crystal structures for closely related prokaryotic lipid kinases. We identify a putative dimerisation interface and propose novel regulatory mechanisms governing structural plasticity induced by phosphorylation and interaction with phospholipids and proteins. Our analysis suggests that the catalytic function and regulation of the enzymes might be dependent on conformational mobility and it provides a roadmap for future interrogation of SK1 function and its role in physiology and disease.

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Section: Lipid Substrate Accessmentioning

confidence: 99%

Sphingosine Kinases: Emerging Structure–Function Insights

Adams

Pyne

2016

Trends in Biochemical Sciences

118

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“…The preceding enzyme, LpxH, and its alternative, LpxI, were observed to fully bind their substrates 20 , 21 , 25 . In contrast, the following enzyme in the pathway, LpxK, was observed to primarily bind lipid head groups with the hydrocarbon tails disordered and extending into solvent 52 . Regardless, LpxB, LpxH, and LpxK do not exhibit strong selectivity for chain length 19 , 53 .…”

Section: Discussionmentioning

confidence: 94%

Crystal structure of lipid A disaccharide synthase LpxB from Escherichia coli

Bohl

Shi²,

Lee

et al. 2018

Nat Commun

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Most Gram-negative bacteria are surrounded by a glycolipid called lipopolysaccharide (LPS), which forms a barrier to hydrophobic toxins and, in pathogenic bacteria, is a virulence factor. During LPS biosynthesis, a membrane-associated glycosyltransferase (LpxB) forms a tetra-acylated disaccharide that is further acylated to form the membrane anchor moiety of LPS. Here we solve the structure of a soluble and catalytically competent LpxB by X-ray crystallography. The structure reveals that LpxB has a glycosyltransferase-B family fold but with a highly intertwined, C-terminally swapped dimer comprising four domains. We identify key catalytic residues with a product, UDP, bound in the active site, as well as clusters of hydrophobic residues that likely mediate productive membrane association or capture of lipidic substrates. These studies provide the basis for rational design of antibiotics targeting a crucial step in LPS biosynthesis.

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“…These structures allowed the positioning of the ATP active site in the enzyme and helped to gain an insight into the possible binding mode of the natural substrate, disaccharide-1-phosphate ( Figure 10A). [97] Besides the modest resolution of the crystal and the fact that the positions of all the side chains of the product are not defined due to the lack of good electron density for these flexible moieties, the disaccharide core is well defined. The sulfonic moiety of HEPES binds to the enzyme through strong electrostatic and hydrogen bonding interactions with the latter residues.…”

Section: The Lpxk Enzymementioning

confidence: 99%

The Inhibition of Lipid A Biosynthesis—The Antidote Against Superbugs?

González‐Bello

2018

Advanced Therapeutics

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After many years of success in the battle against infectious diseases, ground is being lost in this fight with the worldwide increasing appearance of "superbugs," which are resistant to most antibiotics in clinical use. The impact of superbugs on the older population, healthcare-associated patients or patients with a compromised immune system is highly worrisome since no treatment options are available in some cases, especially for Gram-negative pathogens. Efforts are currently devoted to develop novel chemical entities with new mechanisms of action that can inactivate unexplored or underexplored bacterial objectives and to better understand bacterial behavior. The present article highlights the therapeutic potential of the enzymes involved in the biosynthesis of lipid A, which is the lipidic component of lipopolysaccharide-a lipid-anchored complex carbohydrate and a well-designed natural barrier to protect Gram-negative bacteria from external agents, such as antibiotics. An overview of the state-of-the-art inhibitors currently available along with the biochemical and structural knowledge of the enzyme/ligand complexes available is provided. This insight will contribute to the rational design of the next generation of inhibitors or the development of new ones for those promising targets for which inhibitors have not yet been developed.

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Structural Basis of Lipid Binding for the Membrane-embedded Tetraacyldisaccharide-1-phosphate 4′-Kinase LpxK

Cited by 8 publications

References 38 publications

Sphingosine Kinases: Emerging Structure–Function Insights

Sphingosine Kinases: Emerging Structure–Function Insights

Crystal structure of lipid A disaccharide synthase LpxB from Escherichia coli

The Inhibition of Lipid A Biosynthesis—The Antidote Against Superbugs?

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