Decaprenylphosphoryl-beta-D-ribose oxidase

Function

Component of the DprE1-DprE2 complex that catalyzes the 2-step epimerization of decaprenyl-phospho-ribose (DPR) to decaprenyl-phospho-arabinose (DPA), a key precursor that serves as the arabinose donor required for the synthesis of cell-wall arabinans. DprE1 catalyzes the first step of epimerization, namely FAD-dependent oxidation of the C2' hydroxyl of DPR to yield the keto intermediate decaprenyl-phospho-2'-keto-D-arabinose (DPX). The intermediate DPX is then transferred to DprE2 subunit of the epimerase complex, most probably through a 'substrate channel' at the interface of DprE1-DprE2 complex. Can also use farnesyl-phosphoryl-beta-D-ribofuranose (FPR) as substrate in vitro. Appears to be essential for the growth and survival of M.tuberculosis.

Classification

Family (Pfam)

PF04030 ALO, PF01565 FAD_binding_4

InterPro

ALO_C, FAD-bd_PCMH, FAD-bd_PCMH-like_sf, FAD-bd_PCMH_sub2, FAD_lactone_oxidase-like, Oxid_FAD_bind_N

Functional cluster

Acyltransferases & Methyltransferases

Experimental structures · PDB · 27

• 4FDN X-ray 2.40A
• 4FDO X-ray 2.40A
• 4FDP X-ray 2.23A
• 4FEH X-ray 2.04A
• 4FF6 X-ray 2.60A
• 4KW5 X-ray 2.61A
• 4NCR X-ray 1.88A
• 4P8C X-ray 1.95A
• 4P8H X-ray 3.00A
• 4P8K X-ray 2.49A
• 4P8L X-ray 2.02A
• 4P8M X-ray 2.09A
• … and 15 more

A predicted model is available from AlphaFold.

Gene Ontology · 10

• GO:0042597 periplasmic space
• GO:0005886 plasma membrane
• GO:0003885 D-arabinono-1,4-lactone oxidase activity
• GO:0071949 FAD binding
• GO:0016491 oxidoreductase activity
• GO:0035884 arabinan biosynthetic process
• GO:0045227 capsule polysaccharide biosynthetic process
• GO:0071555 cell wall organization
• GO:0070592 cell wall polysaccharide biosynthetic process
• GO:0046677 response to antibiotic

Drugs targeting this protein · 2

• TBA-7371 inhibitor
• MACOZINONE inhibitor

Related proteins · sequence + function similarity

• Decaprenylphosphoryl-beta-D-ribose oxidase 0.97
• L-gulono-1,4-lactone dehydrogenase 0.68
• L-gulono-1,4-lactone dehydrogenase 0.68
• (R)-6-hydroxynicotine oxidase 0.58
• Uncharacterized oxidoreductase ORF5 in fasciation locus 0.57
• Mitomycin radical oxidase 0.56
• Alditol oxidase 0.55
• D-arabinono-1,4-lactone oxidase 0.54
• Alditol oxidase 0.53
• FAD-linked oxidoreductase ptmO 0.51
• D-arabinono-1,4-lactone oxidase 0.50
• Aclacinomycin-N/aclacinomycin-A oxidase 0.50

Co-cited proteins · studied together in the literature

• Decaprenylphosphoryl-2-keto-beta-D-erythro-pentose reductase 7 shared papers
• Alpha-ketoglutarate-dependent sulfate ester dioxygenase 1 shared papers
• HTH-type transcriptional repressor Rv3405c 1 shared papers
• Decaprenylphosphoryl-beta-D-ribose oxidase 1 shared papers
• Arabinogalactan biosynthesis recruiting protein Rv3789 1 shared papers
• Dihydroxy-acid dehydratase 1 shared papers
• RecBCD enzyme subunit RecD 1 shared papers
• ATP-dependent helicase DinG 1 shared papers
• Uncharacterized protein Rv3778c 1 shared papers
• Putative conjugal transfer protein Rv3659c 1 shared papers
• Uncharacterized protein Rv3660c 1 shared papers
• Inosine-5'-monophosphate dehydrogenase 1 shared papers

Literature · 23 cited papers

• Structural studies of Mycobacterium tuberculosis DprE1 interacting with its inhibitors. Drug Discov. Today · 2017
• Characterization of DprE1-mediated benzothiazinone resistance in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. · 2016
• The 8-pyrrole-benzothiazinones are noncovalent inhibitors of DprE1 from Mycobacterium tuberculosis. Antimicrob. Agents Chemother. · 2015
• DprE1 is a vulnerable tuberculosis drug target due to its cell wall localization. ACS Chem. Biol. · 2015
• Structure, dynamics, and interaction of Mycobacterium tuberculosis (Mtb) DprE1 and DprE2 examined by molecular modeling, simulation, and electrostatic studies. PLoS ONE · 2015
• 2-Carboxyquinoxalines kill Mycobacterium tuberculosis through noncovalent inhibition of DprE1. ACS Chem. Biol. · 2015
• Discovery of pyrazolopyridones as a novel class of noncovalent DprE1 inhibitor with potent anti-mycobacterial activity. J. Med. Chem. · 2014
• Assessing the essentiality of the decaprenyl-phospho-D-arabinofuranose pathway in Mycobacterium tuberculosis using conditional mutants. Mol. Microbiol. · 2014
• Towards a new combination therapy for tuberculosis with next generation benzothiazinones. EMBO Mol. Med. · 2014
• DprE1--from the discovery to the promising tuberculosis drug target. Curr. Pharm. Des. · 2014
• Azaindoles: noncovalent DprE1 inhibitors from scaffold morphing efforts, kill Mycobacterium tuberculosis and are efficacious in vivo. J. Med. Chem. · 2013
• The DprE1 enzyme, one of the most vulnerable targets of Mycobacterium tuberculosis. Appl. Microbiol. Biotechnol. · 2013
• … and 11 more in the literature graph