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Article ; Online: Structure and Function of ArnD. A Deformylase Essential for Lipid A Modification with 4-Amino-4-deoxy-l-arabinose and Polymyxin Resistance.

Muñoz-Escudero, Daniel / Breazeale, Steven D / Lee, Myeongseon / Guan, Ziqiang / Raetz, Christian R H / Sousa, Marcelo C

Biochemistry

2023 Volume 62, Issue 20, Page(s) 2970–2981

Abstract: Covalent modification of lipid A with 4-deoxy-4-amino-l-arabinose (Ara4N) mediates resistance to cationic antimicrobial peptides and polymyxin antibiotics in Gram-negative bacteria. The proteins required for Ara4N biosynthesis are encoded in ... ...

Abstract	Covalent modification of lipid A with 4-deoxy-4-amino-l-arabinose (Ara4N) mediates resistance to cationic antimicrobial peptides and polymyxin antibiotics in Gram-negative bacteria. The proteins required for Ara4N biosynthesis are encoded in the
MeSH term(s)	Polymyxins/pharmacology ; Polymyxins/metabolism ; Lipid A/metabolism ; Arabinose/metabolism ; Amino Sugars/chemistry ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/metabolism ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Carbohydrates ; Bacterial Proteins/chemistry
Chemical Substances	Polymyxins ; 4-amino-4-deoxyarabinose (33406-49-4) ; Lipid A ; Arabinose (B40ROO395Z) ; Amino Sugars ; Anti-Bacterial Agents ; Carbohydrates ; Bacterial Proteins
Language	English
Publishing date	2023-10-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.3c00293
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Article ; Online: Structure guided design of an antibacterial peptide that targets UDP-N-acetylglucosamine acyltransferase.

Dangkulwanich, Manchuta / Raetz, Christian R H / Williams, Allison H

Scientific reports

2019 Volume 9, Issue 1, Page(s) 3947

Abstract: ... A biosynthesis, the transfer of an R-3-hydroxyacyl chain from its acyl carrier protein (ACP) to the 3-OH group ...

Abstract	UDP-N-acetylglucosamine (UDP-GlcNAc) acyltransferase (LpxA) catalyzes the first step of lipid A biosynthesis, the transfer of an R-3-hydroxyacyl chain from its acyl carrier protein (ACP) to the 3-OH group of UDP-GlcNAc. Essential in the growth of Gram-negative bacteria, LpxA is a logical target for antibiotics design. A pentadecapeptide (Peptide 920) with high affinity towards LpxA was previously identified in a phage display library. Here we created a small library of systematically designed peptides with the length of four to thirteen amino acids using Peptide 920 as a scaffold. The concentrations of these peptides at which 50% of LpxA is inhibited (IC
MeSH term(s)	Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/pharmacology ; Drug Design ; Gram-Negative Bacteria/drug effects ; Gram-Negative Bacteria/enzymology ; Inhibitory Concentration 50 ; Lipid A/antagonists & inhibitors ; Lipid A/biosynthesis ; Peptide Library ; Peptides/chemistry ; Peptides/pharmacology ; Uridine Diphosphate N-Acetylglucosamine/antagonists & inhibitors
Chemical Substances	Anti-Bacterial Agents ; Lipid A ; Peptide Library ; Peptides ; Uridine Diphosphate N-Acetylglucosamine (528-04-1)
Language	English
Publishing date	2019-03-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-40418-8
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Article ; Online: Structure guided design of an antibacterial peptide that targets UDP-N-acetylglucosamine acyltransferase

Manchuta Dangkulwanich / Christian R. H. Raetz / Allison H. Williams

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 10

Abstract: ... of lipid A biosynthesis, the transfer of an R-3-hydroxyacyl chain from its acyl carrier protein (ACP ...

Abstract	Abstract UDP-N-acetylglucosamine (UDP-GlcNAc) acyltransferase (LpxA) catalyzes the first step of lipid A biosynthesis, the transfer of an R-3-hydroxyacyl chain from its acyl carrier protein (ACP) to the 3-OH group of UDP-GlcNAc. Essential in the growth of Gram-negative bacteria, LpxA is a logical target for antibiotics design. A pentadecapeptide (Peptide 920) with high affinity towards LpxA was previously identified in a phage display library. Here we created a small library of systematically designed peptides with the length of four to thirteen amino acids using Peptide 920 as a scaffold. The concentrations of these peptides at which 50% of LpxA is inhibited (IC50) range from 50 nM to >100 μM. We determined the crystal structure of E. coli LpxA in a complex with a potent inhibitor. LpxA-inhibitor interaction, solvent model and all contributing factors to inhibitor efficacy were well resolved. The peptide primarily occludes the ACP binding site of LpxA. Interactions between LpxA and the inhibitor are different from those in the structure of Peptide 920. The inhibitory peptide library and the crystal structure of inhibitor-bound LpxA described here may further assist in the rational design of inhibitors with antimicrobial activity that target LpxA and potentially other acyltransferases.
Keywords	Medicine ; R ; Science ; Q
Subject code	540
Language	English
Publishing date	2019-03-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
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Article ; Online: Biochemical and Structural Insights into an Fe(II)/α-Ketoglutarate/O

Joo, Sang Hoon / Pemble, Charles W / Yang, Eun Gyeong / Raetz, Christian R H / Chung, Hak Suk

Journal of molecular biology

2018 Volume 430, Issue 21, Page(s) 4036–4048

Abstract: During lipopolysaccharide biosynthesis in several pathogens, including Burkholderia and Yersinia, 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) 3-hydroxylase, otherwise referred to as KdoO, converts Kdo to d-glycero-d-talo-oct-2-ulosonic acid (Ko) in an Fe( ... ...

Abstract	During lipopolysaccharide biosynthesis in several pathogens, including Burkholderia and Yersinia, 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) 3-hydroxylase, otherwise referred to as KdoO, converts Kdo to d-glycero-d-talo-oct-2-ulosonic acid (Ko) in an Fe(II)/α-ketoglutarate (α-KG)/O
MeSH term(s)	Amino Acid Sequence ; Apoproteins/chemistry ; Apoproteins/metabolism ; Biochemical Phenomena ; Dioxygenases/chemistry ; Dioxygenases/metabolism ; Ferrous Compounds/chemistry ; Ferrous Compounds/metabolism ; Ketoglutaric Acids/chemistry ; Ketoglutaric Acids/metabolism ; Mixed Function Oxygenases/chemistry ; Mixed Function Oxygenases/metabolism ; Models, Molecular ; Molecular Structure ; Oxygen/chemistry ; Oxygen/metabolism
Chemical Substances	Apoproteins ; Ferrous Compounds ; Ketoglutaric Acids ; Mixed Function Oxygenases (EC 1.-) ; Dioxygenases (EC 1.13.11.-) ; Oxygen (S88TT14065)
Language	English
Publishing date	2018-08-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2018.07.029
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Article: The calcium-stimulated lipid A 3-O deacylase from Rhizobium etli is not essential for plant nodulation.

Sohlenkamp, Christian / Raetz, Christian R H / Ingram, Brian O

Biochimica et biophysica acta

2013 Volume 1831, Issue 7, Page(s) 1250–1259

Abstract: ... living R. etli is structurally heterogeneous and exists as a mixture of species which are ... either pentaacylated or tetraacylated. In contrast, the lipid A from R. etli bacteroids is reported to consist ... for 3-O deacylation in R. etli is a homolog of the PagL protein originally described ...

Abstract	The lipid A component of lipopolysaccharide from the nitrogen-fixing plant endosymbiont, Rhizobium etli, is structurally very different from that found in most enteric bacteria. The lipid A from free-living R. etli is structurally heterogeneous and exists as a mixture of species which are either pentaacylated or tetraacylated. In contrast, the lipid A from R. etli bacteroids is reported to consist exclusively of tetraacylated lipid A species. The tetraacylated lipid A species in both cases lack a β-hydroxymyristoyl chain at the 3-position of lipid A. Here, we show that the lipid A modification enzyme responsible for 3-O deacylation in R. etli is a homolog of the PagL protein originally described in Salmonella enterica sv. typhimurium. In contrast to the PagL proteins described from other species, R. etli PagL displays a calcium dependency. To determine the importance of the lipid A modification catalyzed by PagL, we isolated and characterized a R. etli mutant deficient in the pagL gene. Mass spectrometric analysis confirmed that the mutant strain was exclusively tetraacylated and radiochemical analysis revealed that 3-O deacylase activity was absent in membranes prepared from the mutant. The R. etli mutant was not impaired in its ability to form nitrogen-fixing nodules on Phaseolus vulgaris but it displayed slower nodulation kinetics relative to the wild-type strain. The lipid A modification catalyzed by R. etli PagL, therefore, is not required for nodulation but may play other roles such as protecting bacterial endosymbionts from plant immune responses during infection.
Language	English
Publishing date	2013-04-12
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbalip.2013.04.002
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Article: The calcium-stimulated lipid A 3-O deacylase from Rhizobium etli is not essential for plant nodulation.

Sohlenkamp, Christian / Raetz, Christian R H / Ingram, Brian O

Biochimica et biophysica acta

2013 Volume 1831, Issue 7, Page(s) 1250–1259

Abstract	The lipid A component of lipopolysaccharide from the nitrogen-fixing plant endosymbiont, Rhizobium etli, is structurally very different from that found in most enteric bacteria. The lipid A from free-living R. etli is structurally heterogeneous and exists as a mixture of species which are either pentaacylated or tetraacylated. In contrast, the lipid A from R. etli bacteroids is reported to consist exclusively of tetraacylated lipid A species. The tetraacylated lipid A species in both cases lack a beta-hydroxymyristoyl chain at the 3-position of lipid A. Here, we show that the lipid A modification enzyme responsible for 3-O deacylation in R. etli is a homolog of the PagL protein originally described in Salmonella enterica sv. typhimurium. In contrast to the PagL proteins described from other species, R. etli PagL displays a calcium dependency. To determine the importance of the lipid A modification catalyzed by PagL, we isolated and characterized a R. etli mutant deficient in the pagL gene. Mass spectrometric analysis confirmed that the mutant strain was exclusively tetraacylated and radiochemical analysis revealed that 3-O deacylase activity was absent in membranes prepared from the mutant. The R. etli mutant was not impaired in its ability to form nitrogen-fixing nodules on Phaseolus vulgaris but it displayed slower nodulation kinetics relative to the wild-type strain. The lipid A modification catalyzed by R. etli PagL, therefore, is not required for nodulation but may play other roles such as protecting bacterial endosymbionts from plant immune responses during infection.
MeSH term(s)	Amino Acid Sequence ; Calcium/metabolism ; Carboxylic Ester Hydrolases/chemistry ; Carboxylic Ester Hydrolases/genetics ; Carboxylic Ester Hydrolases/metabolism ; Gene Deletion ; Lipid A/metabolism ; Molecular Sequence Data ; Mutation ; Nitrogen Fixation ; Phaseolus/microbiology ; Phaseolus/physiology ; Plant Root Nodulation ; Rhizobium etli/chemistry ; Rhizobium etli/enzymology ; Rhizobium etli/genetics ; Rhizobium etli/physiology ; Salmonella typhimurium/enzymology ; Sequence Alignment ; Symbiosis
Chemical Substances	Lipid A ; Carboxylic Ester Hydrolases (EC 3.1.1.-) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2013-07
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
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Article ; Online: In vitro assembly of the outer core of the lipopolysaccharide from Escherichia coli K-12 and Salmonella typhimurium.

Qian, Jinghua / Garrett, Teresa A / Raetz, Christian R H

Biochemistry

2014 Volume 53, Issue 8, Page(s) 1250–1262

Abstract: There are five distinct core structures in the lipopolysaccharides of Escherichia coli and at least two in Salmonella isolates, which vary principally in the outer core oligosaccharide. Six outer core glycosyltransferases, E. coli K-12 WaaG, WaaB, and ... ...

Abstract	There are five distinct core structures in the lipopolysaccharides of Escherichia coli and at least two in Salmonella isolates, which vary principally in the outer core oligosaccharide. Six outer core glycosyltransferases, E. coli K-12 WaaG, WaaB, and WaaO and Salmonella typhimurium WaaI, WaaJ, and WaaK, were cloned, overexpressed, and purified. A novel substrate for WaaG was isolated from ΔwaaG E. coli overexpressing the lipid A phosphatase lpxE and the lipid A late acyltransferase lpxM. The action of lpxE and lpxM in the ΔwaaG background yielded heptose2-1-dephospho Kdo2-lipid A, a 1-dephosphorylated hexa-acylated lipid A with the inner core sugars that is easily isolated by organic extraction. Using this structurally defined acceptor and commercially available sugar nucleotides, each outer core glycosyltransferases was assayed in vitro. We show that WaaG and WaaB add a glucose and galactose sequentially to heptose2-1-dephospho Kdo2-lipid A. E. coli K-12 WaaO and S. typhimurium WaaI add a galactose to the WaaG/WaaB product but can also add a galactose to the WaaG product directly without the branched core sugar added by WaaB. Both WaaI and WaaO require divalent metal ions for optimal activity; however, WaaO, unlike WaaI, can add several glucose residues to its lipid acceptor. Using the product of WaaG, WaaB, and WaaI, we show that S. typhimurium WaaJ and WaaK transfer a glucose and N-acetylglucosamine, respectively, to yield the full outer core. This is the first demonstration of the in vitro assembly of the outer core of the lipopolysaccharide using defined lipid A-oligosaccharide acceptors and sugar donors.
MeSH term(s)	Biocatalysis ; Escherichia coli K12/enzymology ; Escherichia coli K12/metabolism ; Galactose/metabolism ; Glycosyltransferases/metabolism ; Lipopolysaccharides/chemistry ; Lipopolysaccharides/metabolism ; Oligosaccharides/metabolism ; Salmonella typhimurium/enzymology ; Salmonella typhimurium/metabolism ; Uridine Diphosphate N-Acetylglucosamine/metabolism
Chemical Substances	Lipopolysaccharides ; Oligosaccharides ; Uridine Diphosphate N-Acetylglucosamine (528-04-1) ; Glycosyltransferases (EC 2.4.-) ; Galactose (X2RN3Q8DNE)
Language	English
Publishing date	2014-02-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/bi4015665
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Article ; Online: A two-component Kdo hydrolase in the inner membrane of Francisella novicida.

Zhao, Jinshi / Raetz, Christian R H

Molecular microbiology

2010 Volume 78, Issue 4, Page(s) 820–836

Abstract: Lipid A coats the outer surface of the outer membrane of Gram-negative bacteria. In Francisella tularensis subspecies novicida lipid A is present either as the covalently attached anchor of lipopolysaccharide (LPS) or as free lipid A. The lipid A moiety ... ...

Abstract	Lipid A coats the outer surface of the outer membrane of Gram-negative bacteria. In Francisella tularensis subspecies novicida lipid A is present either as the covalently attached anchor of lipopolysaccharide (LPS) or as free lipid A. The lipid A moiety of Francisella LPS is linked to the core domain by a single 2-keto-3-deoxy-D-manno-octulosonic acid (Kdo) residue. F. novicida KdtA is bi-functional, but F. novicida contains a membrane-bound Kdo hydrolase that removes the outer Kdo unit. The hydrolase consists of two proteins (KdoH1 and KdoH2), which are expressed from adjacent, co-transcribed genes. KdoH1 (related to sialidases) has a single predicted N-terminal transmembrane segment. KdoH2 contains 7 putative transmembrane sequences. Neither protein alone catalyses Kdo cleavage when expressed in E. coli. Activity requires simultaneous expression of both proteins or mixing of membranes from strains expressing the individual proteins under in vitro assay conditions in the presence of non-ionic detergent. In E. coli expressing KdoH1 and KdoH2, hydrolase activity is localized in the inner membrane. WBB06, a heptose-deficient E. coli mutant that makes Kdo(2) -lipid A as its sole LPS, accumulates Kdo-lipid A when expressing the both hydrolase components, and 1-dephospho-Kdo-lipid A when expressing both the hydrolase and the Francisella lipid A 1-phosphatase (LpxE).
MeSH term(s)	DNA, Bacterial/chemistry ; DNA, Bacterial/genetics ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Escherichia coli Proteins ; Francisella tularensis/enzymology ; Francisella tularensis/metabolism ; Glycoside Hydrolases/genetics ; Glycoside Hydrolases/metabolism ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Molecular Sequence Data ; Sequence Analysis, DNA
Chemical Substances	DNA, Bacterial ; Escherichia coli Proteins ; Membrane Proteins ; inner membrane protein, E coli ; Glycoside Hydrolases (EC 3.2.1.-)
Language	English
Publishing date	2010-08-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	619315-8
ISSN	1365-2958 ; 0950-382X
ISSN (online)	1365-2958
ISSN	0950-382X
DOI	10.1111/j.1365-2958.2010.07305.x
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Article: Remembering Konrad Bloch.

Raetz, Christian R H

Biochemical and biophysical research communications

2002 Volume 292, Issue 5, Page(s) 1167–1170

MeSH term(s)	Biochemistry/history ; Congresses as Topic/history ; Escherichia coli/metabolism ; History, 20th Century ; Lipids/biosynthesis ; Lipids/history ; United States
Chemical Substances	Lipids
Language	English
Publishing date	2002-04-19
Publishing country	United States
Document type	Autobiography ; Biography ; Historical Article ; Journal Article
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1006/bbrc.2001.2020
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Article ; Online: Chasing acyl carrier protein through a catalytic cycle of lipid A production.

Masoudi, Ali / Raetz, Christian R H / Zhou, Pei / Pemble, Charles W

Nature

2013 Volume 505, Issue 7483, Page(s) 422–426

Abstract: ... as an important therapeutic target. During lipid A synthesis (Raetz pathway), acyl carrier protein shuttles acyl ...

Abstract	Acyl carrier protein represents one of the most highly conserved proteins across all domains of life and is nature's way of transporting hydrocarbon chains in vivo. Notably, type II acyl carrier proteins serve as a crucial interaction hub in primary cellular metabolism by communicating transiently between partner enzymes of the numerous biosynthetic pathways. However, the highly transient nature of such interactions and the inherent conformational mobility of acyl carrier protein have stymied previous attempts to visualize structurally acyl carrier protein tied to an overall catalytic cycle. This is essential to understanding a fundamental aspect of cellular metabolism leading to compounds that are not only useful to the cell, but also of therapeutic value. For example, acyl carrier protein is central to the biosynthesis of the lipid A (endotoxin) component of lipopolysaccharides in Gram-negative microorganisms, which is required for their growth and survival, and is an activator of the mammalian host's immune system, thus emerging as an important therapeutic target. During lipid A synthesis (Raetz pathway), acyl carrier protein shuttles acyl intermediates linked to its prosthetic 4'-phosphopantetheine group among four acyltransferases, including LpxD. Here we report the crystal structures of three forms of Escherichia coli acyl carrier protein engaging LpxD, which represent stalled substrate and liberated products along the reaction coordinate. The structures show the intricate interactions at the interface that optimally position acyl carrier protein for acyl delivery and that directly involve the pantetheinyl group. Conformational differences among the stalled acyl carrier proteins provide the molecular basis for the association-dissociation process. An unanticipated conformational shift of 4'-phosphopantetheine groups within the LpxD catalytic chamber shows an unprecedented role of acyl carrier protein in product release.
MeSH term(s)	Acyl Carrier Protein/chemistry ; Acyl Carrier Protein/metabolism ; Acyltransferases/chemistry ; Acyltransferases/metabolism ; Biocatalysis ; Crystallography, X-Ray ; Escherichia coli/chemistry ; Hydrolysis ; Lipid A/biosynthesis ; Lipid A/metabolism ; Models, Molecular ; Protein Binding ; Protein Conformation
Chemical Substances	Acyl Carrier Protein ; Lipid A ; Acyltransferases (EC 2.3.-) ; acyl-(acyl-carrier-protein)-UDP-N-acetylglucosamine acyltransferase (EC 2.3.1.129)
Language	English
Publishing date	2013-11-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature12679
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