Metal ion homeostasis: Metalloenzyme paralogs in the bacterial adaptative response to zinc restriction

Abstract

Zn is an essential catalytic or structural cofactor for ≈ 6–10% of all proteins in a typical proteome. Bacteria often encounter extreme Zn limitation in their native environments and must adapt to the challenge of survival when there is insufficient Zn to metalate all cellular Zn binding sites. As a result, bacteria have evolved multiple mechanisms of cellular adaptation to low Zn to acquire, redistribute, or prioritize Zn for essential processes. One such mechanism is the increased cellular abundance of enzyme “paralogs” that complement the function of obligatory Zn-dependent enzymes that cannot be fully metalated in the Zn restricted environment. Here, we carefully review identified Zur (zinc uptake repressor)-regulated paralogs, compare each to their canonical enzyme counterpart, and infer how the paralog contributes to cellular function under conditions of Zn restriction. These paralogs can be catalogued in three distinct ways: (1) those that dispense of the need for a metal cofactor altogether; (2) those that still utilize Zn but have evolved new structural properties to minimize metal dissociation; and (3) those that replace Zn with a different metal. We evaluate the mechanistic distinctions between canonical protein and paralog and close by placing all known paralogs within the context of bacterial metabolism. We find that paralogs cluster within ancient and essential pathways and processes, notably nucleotide metabolism and the central dogma, as a way to prioritize Zn within the cell and sustain growth in Zn-deplete environments.