The control of the intracellular level of cyclic dinucleotides is a major strategy to transduce external signals into a cellular response, particularly in bacteria. The HD-GYP metalloproteins, a subgroup of the larger family of histidine-aspartate (HD) hydrolases, can catalyze the cleavage of the phosphodiester bond(s) of cyclic dinucleotides. The HD signature is involved in metal binding in the active site, whereas the GYP motif is likely involved in recognition and interaction with other partners. The most representative substrate of HD-GYPs is the second messenger cyclic-di-GMP (c-di-GMP), a global regulator of bacterial biofilm, motility, and virulence. Hydrolysis of c-di-GMP into the linear form pGpG or into the monomeric guanosine derivative (GMP) reprograms the cellular phenotype, usually promoting biofilm dispersion and virulence. Recent data indicate that members of HD-GYP group can also hydrolyze the bacterial cyclic diGMP-AMP (cGAMP) dinucleotide or act as possible sensors of pGpG.

The HD-GYP diversity is not limited to substrate recognition: the most striking trait is the extraordinary heterogeneity of the active sites characterized so far, showing different metals ions assisting catalysis, both in terms of their nature and number. In this review, we provide a critical overview of the structural, functional, and kinetic properties of the bacterial HD-GYP metalloproteins.

控制环二核苷酸的细胞内水平是将外部信号转导成细胞反应的主要策略，特别是在细菌中。HD-GYP 金属蛋白是较大的组氨酸-天冬氨酸 (HD) 水解酶家族的一个亚组，可以催化环状二核苷酸的磷酸二酯键的裂解。HD 特征参与活性位点的金属结合，而 GYP 基序可能参与识别和与其他伙伴的相互作用。HD-GYPs 最具代表性的底物是第二信使环状二-GMP (c-di-GMP)，它是细菌生物膜、运动性和毒力的全球调节剂。c-di-GMP 水解成线性形式 pGpG 或单体鸟苷衍生物 (GMP) 会重新编程细胞表型，通常会促进生物膜的分散和毒力。

HD-GYP 的多样性不仅限于底物识别：最引人注目的特征是迄今为止表征的活性位点的异常异质性，无论是在性质上还是在数量上，都显示出不同的金属离子辅助催化。在这篇综述中，我们对细菌 HD-GYP 金属蛋白的结构、功能和动力学特性进行了批判性概述。