Inhibition of Mycobacterium tuberculosis dihydrodipicolinate synthase by alpha-ketopimelic acid and its other structural analogues
IR@IGIB: CSIR-Institute of Genomics & Integrative Biology, New Delhi
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| Title |
Inhibition of Mycobacterium tuberculosis dihydrodipicolinate synthase by alpha-ketopimelic acid and its other structural analogues
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| Creator |
Shrivastava, Priyanka
Navratna, Vikas Silla, Yumnam P. Dewangan, Rikeshwer Pramanik, Atreyi Sarika, Chaudhary GeethaVani, Rayasam Kumar, Anuradha Gopal, Balasubramanian Ramachandran, Srinivasan |
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| Subject |
G1 Genome informatics (General)
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| Description |
The Mycobacterium tuberculosis dihydrodipicolinate synthase (Mtb-dapA) is an essential gene. Mtb-DapA catalyzes the aldol condensation between pyruvate and L-aspartate-beta-semialdehyde (ASA) to yield dihydrodipicolinate. In this work we tested the inhibitory effects of structural analogues of pyruvate on recombinant Mtb-DapA (Mtb-rDapA) using a coupled assay with recombinant dihydrodipicolinate reductase (Mtb-rDapB). Alpha-ketopimelic acid (α-KPA) showed maximum inhibition of 88% and IC50 of 21 μM in the presence of pyruvate (500 μM) and ASA (400 μM). Competition experiments with pyruvate and ASA revealed competition of α-KPA with pyruvate. Liquid chromatography-mass spectrometry (LC-MS) data with multiple reaction monitoring (MRM) showed that the relative abundance peak of final product, 2,3,4,5-tetrahydrodipicolinate, was decreased by 50%. Thermal shift assays showed 1 °C Tm shift of Mtb-rDapA upon binding α-KPA. The 2.4 Å crystal structure of Mtb-rDapA-α-KPA complex showed the interaction of critical residues at the active site with α-KPA. Molecular dynamics simulations over 500 ns of pyruvate docked to Mtb-DapA and of α-KPA-bound Mtb-rDapA revealed formation of hydrogen bonds with pyruvate throughout in contrast to α-KPA. Molecular descriptors analysis showed that ligands with polar surface area of 91.7 Å2 are likely inhibitors. In summary, α-hydroxypimelic acid and other analogues could be explored further as inhibitors of Mtb-DapA.
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| Publisher |
Nature
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| Date |
2016-08-09
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://openaccess.igib.res.in/165/1/srep30827.pdf
Shrivastava, Priyanka and Navratna, Vikas and Silla, Yumnam and P. Dewangan, Rikeshwer and Pramanik, Atreyi and Sarika, Chaudhary and GeethaVani, Rayasam and Kumar, Anuradha and Gopal, Balasubramanian and Ramachandran, Srinivasan (2016) Inhibition of Mycobacterium tuberculosis dihydrodipicolinate synthase by alpha-ketopimelic acid and its other structural analogues. Nature, 6 (30827). ISSN doi:10.1038/srep30827 |
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| Relation |
https://www.nature.com/articles/srep30827
http://openaccess.igib.res.in/165/ |
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