Crystal Structures of Undecaprenyl Pyrophosphate Synthase in Complex with Magnesium, Isopentenyl Pyrophosphate, and Farnesyl Thiopyrophosphate

Guo, Rey‐Ting; Ko, Tzu‐Ping; Chen, Annie P.-C.; Kuo, C.J.; Wang, Andrew H.-J.; Liang, Po‐Huang

doi:10.1074/jbc.m502121200

Cited by 125 publications

(175 citation statements)

References 37 publications

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“…The PT barrel fold of FgaPT2 and NphB is entirely different from the all-␣-helical structure of farnesyl diphosphate synthase (12) and from the structure of cis-polyprenyl diphosphate synthases (37), which, like FgaPT2 and NphB, do not contain an (N/D)DxxD motif. Likewise, this fold bears no resemblance to the recently suggested structures of the membrane-bound aromatic PTs UbiA and LePGT1, which catalyze the 3-prenylation of 4-hydroxybenzoate (38,39).…”

Section: Mutagenesis Of Fgapt2mentioning

confidence: 99%

The structure of dimethylallyl tryptophan synthase reveals a common architecture of aromatic prenyltransferases in fungi and bacteria

Metzger

Schall²,

Zocher³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

178

282

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Ergot alkaloids are toxins and important pharmaceuticals that are produced biotechnologically on an industrial scale. The first committed step of ergot alkaloid biosynthesis is catalyzed by dimethylallyl tryptophan synthase (DMATS; EC 2.5.1.34). Orthologs of DMATS are found in many fungal genomes. We report here the x-ray structure of DMATS, determined at a resolution of 1.76 Å. A complex of DMATS from Aspergillus fumigatus with its aromatic substrate L-tryptophan and with an analogue of its isoprenoid substrate dimethylallyl diphosphate reveals the structural basis of this enzyme-catalyzed Friedel-Crafts reaction, which shows strict regiospecificity for position 4 of the indole nucleus of tryptophan as well as unusual independence of the presence of Mg 2؉ ions. The 3D structure of DMATS belongs to a rare ␤/␣ barrel fold, called prenyltransferase barrel, that was recently discovered in a small group of bacterial enzymes with no sequence similarity to DMATS. These bacterial enzymes catalyze the prenylation of aromatic substrates in the biosynthesis of secondary metabolites (i.e., a reaction similar to that of DMATS).EC 2.5.1.34 ͉ ergot alkaloids ͉ PT barrel ͉ ABBA prenyltransferase

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Section: Mutagenesis Of Fgapt2mentioning

confidence: 99%

The structure of dimethylallyl tryptophan synthase reveals a common architecture of aromatic prenyltransferases in fungi and bacteria

Metzger

Schall²,

Zocher³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

178

282

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“…Four subsequent steps lead to the synthesis of IPP and DMAPP, the universal precursors to FPP. The synthesis of undecaprenyl pyrophosphate in bacteria originates from all-trans-FPP by the addition of eight isopentenyl units catalysed by the soluble enzyme undecaprenyl pyrophosphate synthase UppS (Guo et al, 2005;Teng & Liang, 2012a, b;Zhu et al, 2013). Undecaprenyl pyrophosphate and dolichol de novo synthesis are distinguished by terminal products (an isoprenyl pyrophosphate versus an alcohol) as well as the saturation state of the a-isoprene units (unsaturated versus saturated).…”

Section: Biosynthesis Of the Eubacterial Undecaprenyl Lipid Carriersmentioning

confidence: 99%

Conservation of the PTEN catalytic motif in the bacterial undecaprenyl pyrophosphate phosphatase, BacA/UppP

Bickford

Nick

2013

Microbiology

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Isoprenoid lipid carriers are essential in protein glycosylation and bacterial cell envelope biosynthesis. The enzymes involved in their metabolism (synthases, kinases and phosphatases) are therefore critical to cell viability. In this review, we focus on two broad groups of isoprenoid pyrophosphate phosphatases. One group, containing phosphatidic acid phosphatase motifs, includes the eukaryotic dolichyl pyrophosphate phosphatases and proposed recycling bacterial undecaprenol pyrophosphate phosphatases, PgpB, YbjB and YeiU/LpxT. The second group comprises the bacterial undecaprenol pyrophosphate phosphatase, BacA/UppP, responsible for initial formation of undecaprenyl phosphate, which we predict contains a tyrosine phosphate phosphatase motif resembling that of the tumour suppressor, phosphatase and tensin homologue (PTEN). Based on protein sequence alignments across species and 2D structure predictions, we propose catalytic and lipid recognition motifs unique to BacA/UppP enzymes. The verification of our proposed active-site residues would provide new strategies for the development of substratespecific inhibitors which mimic both the lipid and pyrophosphate moieties, leading to the development of novel antimicrobial agents.

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“…4C). 37 In the latter complex, the Mg 2 + was not bound to C 5 -PP to which it is primarily bound (in fact, UppS binds C 5 -PP in complex with Mg 2 + ), but was, instead, coordinated by the C 15 -sPP pyrophosphate group and Asp26 side chain. In contrast, in an inactive UppS mutant in which the aspartate residue was replaced by an alanine, the Mg 2 + ion remained associated to C 5 -PP and no Mg 2 + was associated to C 15 -sPP.…”

Section: Synthesis Of Bacterial Undecaprenyl-diphosphatementioning

confidence: 99%

“…UppS activity was also shown to be dependent on the presence of the divalent cation Mg 2 + for C 5 -PP binding and for catalysis, but not for initial C 15 -PP binding. 13,83 Several UppS three-dimensional (3D) structures, with 13,14,37 or without 29,59 bound substrates, were solved, which along with intensive mutagenesis 30,31,58 and kinetic studies 68,103 provided great knowledge on the functioning of this biosynthetic step. The condensation reaction catalyzed by prenyltransferases occurs via a nucleophilic attack of the C1-atom from the allylic substrate bearing the leaving phosphate group by the C4-atom of C 5 -PP (Fig.…”

Section: Synthesis Of Bacterial Undecaprenyl-diphosphatementioning

confidence: 99%

Deciphering the Metabolism of Undecaprenyl-Phosphate: The Bacterial Cell-Wall Unit Carrier at the Membrane Frontier

Manat

Roure

Auger

et al. 2014

Microbial Drug Resistance

124

139

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During the biogenesis of bacterial cell-wall polysaccharides, such as peptidoglycan, cytoplasmic synthesized precursors should be trafficked across the plasma membrane. This essential process requires a dedicated lipid, undecaprenyl-phosphate that is used as a glycan lipid carrier. The sugar is linked to the lipid carrier at the inner face of the membrane and is translocated toward the periplasm, where the glycan moiety is transferred to the growing polymer. Undecaprenyl-phosphate originates from the dephosphorylation of its precursor undecaprenyl-diphosphate, with itself generated by de novo synthesis or by recycling after the final glycan transfer. Undecaprenyl-diphosphate is de novo synthesized by the cytosolic cis-prenyltransferase undecaprenyldiphosphate synthase, which has been structurally and mechanistically characterized in great detail highlighting the condensation process. In contrast, the next step toward the formation of the lipid carrier, the dephosphorylation step, which has been overlooked for many years, has only started revealing surprising features. In contrast to the previous step, two unrelated families of integral membrane proteins exhibit undecaprenyldiphosphate phosphatase activity: BacA and members of the phosphatidic acid phosphatase type 2 super-family, raising the question of the significance of this multiplicity. Moreover, these enzymes establish an unexpected link between the synthesis of bacterial cell-wall polymers and other biological processes. In the present review, the current knowledge in the field of the bacterial lipid carrier, its mechanism of action, biogenesis, recycling, regulation, and future perspective works are presented.

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Crystal Structures of Undecaprenyl Pyrophosphate Synthase in Complex with Magnesium, Isopentenyl Pyrophosphate, and Farnesyl Thiopyrophosphate

Cited by 125 publications

References 37 publications

The structure of dimethylallyl tryptophan synthase reveals a common architecture of aromatic prenyltransferases in fungi and bacteria

The structure of dimethylallyl tryptophan synthase reveals a common architecture of aromatic prenyltransferases in fungi and bacteria

Conservation of the PTEN catalytic motif in the bacterial undecaprenyl pyrophosphate phosphatase, BacA/UppP

Deciphering the Metabolism of Undecaprenyl-Phosphate: The Bacterial Cell-Wall Unit Carrier at the Membrane Frontier

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