PDBsum entry 6de4

Oxidoreductase/oxidoreductase inhibitor

PDB id: 6de4

Contents

Protein chains

186 a.a.

Ligands

NDP ×2

G6Y ×2

GOL ×2

EOH ×4

SO4 ×2

Metals

_CL ×2

_CA ×2

Waters ×70

PDB id:

6de4

Name:

Oxidoreductase/oxidoreductase inhibitor

Title:

Homo sapiens dihydrofolate reductase complexed with beta-NADPH and 3'- [(2r)-4-(2,4-diamino-6-ethylphenyl)but-3-yn-2-yl]-5'-methoxy-[1,1'- biphenyl]-4-carboxylic acid

Structure:

Dihydrofolate reductase. Chain: a, b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: dhfr. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.41Å R-factor: 0.184 R-free: 0.221

Authors:

B.Hajian,D.Wright

Key ref:

B.Hajian et al. (2019). Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents. Cell Chem Biol, 26, 781. PubMed id: 30930162 DOI: 10.1016/j.chembiol.2019.02.013

Date:

11-May-18 Release date: 23-May-18

Protein chains

P00374  (DYR_HUMAN) -  Dihydrofolate reductase from Homo sapiens

Seq: 187 a.a.

Struc: 186 a.a.

Enzyme reactions

• Enzyme class: E.C.1.5.1.3 - dihydrofolate reductase.
• Pathway: Folate Coenzymes
• Reaction: (6S)-5,6,7,8-tetrahydrofolate + NADP⁺ = 7,8-dihydrofolate + NADPH + H⁺

(6S)-5,6,7,8-tetrahydrofolate + NADP(+) (Bound ligand (Het Group name = NDP) corresponds exactly) = 7,8-dihydrofolate + NADPH + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.chembiol.2019.02.013

Cell Chem Biol 26:781 (2019)

PubMed id: 30930162

Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents.

B.Hajian, E.Scocchera, C.Shoen, J.Krucinska, K.Viswanathan, N.G-Dayanandan, H.Erlandsen, A.Estrada, K.Mikušová, J.Korduláková, M.Cynamon, D.Wright.

ABSTRACT

The folate biosynthetic pathway offers many druggable targets that have yet to be exploited in tuberculosis therapy. Herein, we have identified a series of small molecules that interrupt Mycobacterium tuberculosis (Mtb) folate metabolism by dual targeting of dihydrofolate reductase (DHFR), a key enzyme in the folate pathway, and its functional analog, Rv2671. We have also compared the antifolate activity of these compounds with that of para-aminosalicylic acid (PAS). We found that the bioactive metabolite of PAS, in addition to previously reported activity against DHFR, inhibits flavin-dependent thymidylate synthase in Mtb, suggesting a multi-targeted mechanism of action for this drug. Finally, we have shown that antifolate treatment in Mtb decreases the production of mycolic acids, most likely due to perturbation of the activated methyl cycle. We conclude that multi-targeting of the folate pathway in Mtb is associated with highly potent anti-mycobacterial activity.