Bacillithiol, a new role in buffering intracellular zinc

Abstract

Zinc is a catalytic or structural cofactor of numerous proteins but can also be toxic if cells accumulate too much of this essential metal. Therefore, mechanisms of zinc homeostasis are needed to maintain a low but adequate amount of free zinc so that newly translated zinc-dependent proteins can bind their cofactor without confounding issues of toxicity. These mechanisms include the regulation of uptake and efflux transporters and buffering of the free metal concentration by low-molecular-weight ligands in the cytosol. While many of the transporters involved in zinc homeostasis have been discovered in recent years, the molecules that buffer zinc have remained largely a mystery. In the new report highlighted by this commentary, Ma et al. (2014) provide convincing evidence that bacillithiol, the major low-molecular-weight thiol compound in Bacillus subtilis, serves as an important zinc buffer in those cells. Their discovery provides an important piece to the puzzle of how zinc buffering occurs in a large number of microbes and provides new clues about the role and relative importance of zinc buffering in all organisms.

Figure 1

Components of zinc homeostasis in Bacillus subtilis. Zinc uptake is mediated by ZnuABC, a zinc transporter complex under the regulation of the Zur repressor. Zinc efflux is mediated by Cad and CzcD, which are under the control of the CzrA repressor. Both Zur and CzrA are regulated by the free zinc pool that is buffered by BSH. Notably, a significant fraction of the metallation of zinc-binding proteins may occur via direct ligand exchange reactions with donor complexes such as Zn(BSH)₂.

Figure 2

Structure of BSH. BSH is the α-anomeric glycoside of cysteinyl-D-glucosamine with L-malic acid. Figure courtesy of J. Helmann.