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Regulation of zinc-dependent enzymes by metal carrier proteins.

ABSTRACT: Zn²⁺ ions are essential in many physiological processes, including enzyme catalysis, protein structural stabilization, and the regulation of many proteins. The affinities of proteins for Zn²⁺ ions span several orders of magnitude, with catalytic Zn²⁺ ions generally held more tightly than structural or regulatory ones. Metal carrier proteins, most of which are not specific for Zn²⁺, bind these ions with a broad range of affinities that overlap those of catalytic, structural, and regulatory Zn²⁺ ions and are thought to be responsible for distributing the metal through most cells, tissues, and fluid compartments. While little is known about how many proteins obtain or release these ions, there is now considerable experimental evidence suggesting that metal carrier proteins may be responsible for transferring metals to and from some Zn²⁺-dependent proteins, thus serving as a major regulatory factor for them. In this review, the biological roles of Zn²⁺ and structures of Zn²⁺ binding sites are examined, and experimental evidence demonstrating the direct participation of metal carrier proteins in enzyme regulation is discussed. Mechanisms of metal ion transfer are also offered, and the potential physiological significance of this phenomenon is explored.

SUBMITTER: Thompson MW

PROVIDER: S-EPMC8862405 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Regulation of zinc-dependent enzymes by metal carrier proteins.

Thompson Michael W MW

Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 20220222 2

Zn2+ ions are essential in many physiological processes, including enzyme catalysis, protein structural stabilization, and the regulation of many proteins. The affinities of proteins for Zn2+ ions span several orders of magnitude, with catalytic Zn2+ ions generally held more tightly than structural or regulatory ones. Metal carrier proteins, most of which are not specific for Zn2+, bind these ions with a broad range of affinities that overlap those of ...[more]

PMID: 35192096

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Project description:The majority of drug discovery efforts against herpesviruses have focused on nucleoside analogs that target viral DNA polymerases, agents that are associated with dose-limiting toxicity and/or a narrow spectrum of activity. We are pursuing a strategy based on targeting two-metal ion-dependent (TMID) viral enzymes. This family of enzymes consists of structurally related proteins that share common active sites containing conserved carboxylates predicted to coordinate divalent cations essential for catalysis. Compounds that target TMID enzymes, such as HIV integrase and influenza endoribonuclease, have been successfully developed for clinical use. HIV integrase inhibitors have been reported to inhibit replication of herpes simplex virus (HSV) and other herpesviruses; however, the molecular targets of their antiviral activities have not been identified. We employed a candidate-based approach utilizing several two-metal-directed chemotypes and the potential viral TMID enzymatic targets in an effort to correlate target-based activity with antiviral potency. The panel of compounds tested included integrase inhibitors, the anti-influenza agent baloxavir, three natural products previously shown to exhibit anti-HSV activity, and two 8-hydroxyquinolines (8-HQs), AK-157 and AK-166, from our in-house program. The integrase inhibitors exhibited weak overall anti-HSV-1 activity, while the 8-HQs were shown to inhibit both HSV-1 and cytomegalovirus (CMV). Target-based analysis demonstrated that none of the antiviral compounds acted by inhibiting ICP8, contradicting previous reports. On the other hand, baloxavir inhibited the proofreading exonuclease of HSV polymerase, while AK-157 and AK-166 inhibited the alkaline exonuclease UL12. In addition, AK-157 also inhibited the catalytic activity of the HSV polymerase, which provides an opportunity to potentially develop dual-targeting agents against herpesviruses. IMPORTANCE Human herpesviruses (HHVs) establish lifelong latent infections, which undergo periodic reactivation and remain a major cause of morbidity and mortality, especially in immunocompromised individuals. Currently, HHV infections are treated primarily with agents that target viral DNA polymerase, including nucleoside analogs; however, long-term treatment can be complicated by the development of drug resistance. New therapies with novel modes of action would be important not only for the treatment of resistant viruses but also for use in combination therapy to reduce dose-limiting toxicities and potentially eliminate infection. Since many essential HHV proteins are well conserved, inhibitors of novel targets would ideally exhibit broad-spectrum activity against multiple HHVs.

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Regulation of zinc-dependent enzymes by metal carrier proteins.

Publications

Regulation of zinc-dependent enzymes by metal carrier proteins.

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