Progress in aminocyclitol biosynthesis

Mahmud, Taifo

doi:10.1016/j.cbpa.2009.02.030

Cited by 35 publications

(37 citation statements)

References 52 publications

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“…Similarly, the DOIS family is also closely related to DHQS, as both have conserved active site residues, except for those at positions R264 and N268. In DOIS from the tobramycin (TbmA), kanamycin (KanA), ribostamycin (RbmA), gentamycin (GntB), and butirosin (BtrC) pathways, 24, 25 the arginine and asparagine residues corresponding to position 264 and 268 in DHQS have been altered to conserved glycine and glutamate residues, respectively.…”

Section: Resultsmentioning

confidence: 99%

Evolutionary Divergence of Sedoheptulose 7-Phosphate Cyclases Leads to Several Distinct Cyclic Products

et al. 2012

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Sedoheptulose 7-phosphate cyclases are enzymes that utilize the pentose phosphate pathway intermediate, sedoheptulose 7-phosphate, to generate cyclic precursors of many bioactive natural products, such as the antidiabetic drug acarbose, the crop protectant validamycin, and the natural sunscreens mycosporine-like amino acids. These proteins are phylogenetically related to the dehydroquinate (DHQ) synthases from the shikimate pathway, and are part of the more recently recognized superfamily of sugar phosphate cyclases, which includes DHQ synthases, aminoDHQ synthases and 2-deoxy-scyllo-inosose synthases. Through genome mining and biochemical studies, we identified yet another subset of DHQS-like proteins in the actinomycete Actinosynnema mirum and the myxobacterium Stigmatella aurantiaca DW4/3–1. These enzymes catalyze the conversion of sedoheptulose 7-phosphate to 2-epi-valiolone, which is predicted to be an alternative precursor for aminocyclitol biosynthesis. Comparative bioinformatics and biochemical analyses of these proteins with 2-epi-5-epi-valiolone synthases (EEVS) and desmethyl-4-deoxygadusol synthases (DDGS) provided further insights into their genetic diversity, conserved amino acid sequences, and plausible catalytic mechanisms. The results further highlight the uniquely diverse DHQS-like sugar phosphate cyclases, which may provide new tools for chemoenzymatic, stereospecific synthesis of various cyclic molecules.

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Section: Resultsmentioning

confidence: 99%

Evolutionary Divergence of Sedoheptulose 7-Phosphate Cyclases Leads to Several Distinct Cyclic Products

et al. 2012

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“…[12] In general, at least one primary-metabolite MIPS is encoded in the genomes of all bacterial species. Various DHQS orthologues are involved in secondary metabolism, [13] such as 2-deoxystreptamine-containing aminoglycoside antibiotics [11,14] ands unscreen molecules in cyanobacteria [15] and vertebrates. For instance, S. coelicolor A3(2) has three putative MIPSs( SCO3899, SCO6573,S CO3243), and Streptomycesg riseus IFO 13350 has two (SGR3681, SGR1112), although no cyclitol-containing metabolite (apart from myo-inositol-derived molecules)h as been identified.…”

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confidence: 99%

Five‐Membered Cyclitol Phosphate Formation by a myo‐Inositol Phosphate Synthase Orthologue in the Biosynthesis of the Carbocyclic Nucleoside Antibiotic Aristeromycin

et al. 2016

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Aristeromycin is a unique carbocyclic nucleoside antibiotic produced by Streptomyces citricolor. In order to elucidate its intriguing carbocyclic formation, we used a genome-mining approach to identify the responsible enzyme. In silico screening with known cyclitol synthases involved in primary metabolism, such as myo-inositol-1-phosphate synthase (MIPS) and dehydroqunate synthase (DHQS), identified a unique MIPS orthologue (Ari2) encoded in the genome of S. citricolor. Heterologous expression of the gene cluster containing ari2 with a cosmid vector in Streptomyces albus resulted in the production of aristeromycin, thus indicating that the cloned DNA region (37.5 kb) with 33 open reading frames contains its biosynthetic gene cluster. We verified that Ari2 catalyzes the formation of a novel five-membered cyclitol phosphate from d-fructose 6-phosphate (F6P) with NAD as a cofactor. This provides insight into cyclitol phosphate synthase as a member of the MIPS family of enzymes. A biosynthetic pathway to aristeromycin is proposed based on bioinformatics analysis of the gene cluster.

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“…Prompted by the identification of the biosynthetic gene cluster, investigations into validamycin biosynthesis have revealed the involvement of a number of unusual enzymes that exclusively recognize carbasugars (cyclitols) as substrates. 8 The pathway leads to a condensation between two cyclitol intermediates by an undetermined coupling mechanism. The lack of clear understanding of this coupling reaction has led to speculations about how the nitrogen bridge in validamycin A is formed.…”

Section: Introductionmentioning

confidence: 99%

“…The lack of clear understanding of this coupling reaction has led to speculations about how the nitrogen bridge in validamycin A is formed. 8-13 …”

Section: Introductionmentioning

confidence: 99%

Nucleotidylation of unsaturated carbasugar in validamycin biosynthesis

Yang

Zhang

et al. 2011

Org. Biomol. Chem.

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Validamycin A is a member of microbial-derived C7N-aminocyclitol family of natural products that is widely used as crop protectant and the precursor of the antidiabetic drug voglibose. Its biosynthetic gene clusters have been identified in several Streptomyces hygroscopicus strains, and a number of genes within the clusters have been functionally analyzed. Of these genes, valB, which encodes a sugar nucleotidyltransferase, was found through inactivation study to be essential for validamycin biosynthesis, but its role was unclear. To characterize the role of ValB in validamycin biosynthesis, four carbasugar phosphate analogues were synthesized and tested as substrate for ValB. The results showed that ValB efficiently catalyzes the conversion of valienol 1-phosphate to its nucleotidyl diphosphate derivatives, whereas other unsaturated carbasugar phosphates were found to be not the preferred substrate. ValB requires Mg2+, Mn2+, or Co2+ for its optimal activity and uses the purine-based nucleotidyltriphosphates (ATP and GTP) more efficiently than the pyrimidine-based NTPs (CTP, dTTP, and UTP) as nucleotidyl donor. ValB represents the first member of unsaturated carbasugar nucleotidyltransferases involved in natural products biosynthesis. Its characterization not only expands our understanding of aminocyclitol-derived natural products biosynthesis, but may also facilitate the development of new tools for chemoenzymatic synthesis of carbohydrate mimetics.

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Progress in aminocyclitol biosynthesis

Cited by 35 publications

References 52 publications

Evolutionary Divergence of Sedoheptulose 7-Phosphate Cyclases Leads to Several Distinct Cyclic Products

Evolutionary Divergence of Sedoheptulose 7-Phosphate Cyclases Leads to Several Distinct Cyclic Products

Five‐Membered Cyclitol Phosphate Formation by a myo‐Inositol Phosphate Synthase Orthologue in the Biosynthesis of the Carbocyclic Nucleoside Antibiotic Aristeromycin

Nucleotidylation of unsaturated carbasugar in validamycin biosynthesis

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