Chemical Biology: Domino drug action

The antibiotic trimethoprim, used primarily for the treatment of urinary tract infections, works by an unexpected 'domino effect' in which two enzymes in a pathway are both inhibited by a single drug, according to a paper online this week in Nature Chemical Biology. The work reveals new insights into the mechanism of a clinically used drug and highlights the potential of looking at metabolic pathways to understand drug action.

Trimethoprim known to inhibit a bacterial enzyme called dihydrofolate reductase (DHFR). By using a method for simultaneously measuring all of the folate-related chemicals in a bacterial cell, Joshua Rabinowitz and colleagues found that trimethoprim was blocking not just the activity of DHFR, but also another enzyme in folate metabolism. The second enzyme was not directly inhibited by trimethoprim. Instead, inhibiting DHFR caused accumulation of the substrate, dihydrofolate, which was an inhibitor of the second enzyme. Therefore, trimethoprim created a cascade of enzyme inhibition.

Dual gating in one motion

Scientists have discovered how sodium influences a group of potassium channels, according to a paper to be published online this week in Nature Chemical Biology. This discovery improves our understanding of ion channels and may offer new insights into the function of known drugs like cardiac glycosides.

Ion channels are proteins that sit in the cell membrane and allow ions such as sodium and chloride to pass from one side of the membrane to the other; this action can cause the buildup of electrical gradients that result in biological processes like the firing of neurons. The activity of inwardly rectifying potassium (Kir) channels is further controlled by a specific lipid in the membrane. Some of the Kir channels are also controlled by sodium, termed 'dual gating', but it was not clear how these two signals would both be needed for channel activity.

Diomedes Logothetis and colleagues used a combined computational-experimental approach to show that sodium prevents the interaction of an aspartate amino acid with an arginine amino acid by binding to the aspartate amino acid. This frees the arginine amino acid to interact with the lipid, which explains how the signals coordinate. This molecular-level insight expands our view of the function of these important channels, represents a potential new avenue for drug design.

A domino effect in antifolate drug action in Escherichia coli

Yun Kyung Kwon, Wenyun Lu, Eugene Melamud, Nurussaba Khanam, Andrew Bognar & Joshua D Rabinowitz

Published online: 24 August 2008 | doi 10.1038/nchembio.108

Abstract | Full text | PDF | Supplementary information

A sodium-mediated structural switch that controls the sensitivity of Kir channels to PtdIns(4,5)P₂

Avia Rosenhouse-Dantsker, Jin L Sui, Qi Zhao, Radda Rusinova, Aldo A Rodríguez-Menchaca, Zhe Zhang & Diomedes E Logothetis

Published online: 14 September 2008 | doi 10.1038/nchembio.112

Abstract | Full text | PDF | Supplementary information