Carbonic Anhydrases and Metabolism

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Abstract

Although the role of carbonic anhydrases (CAs, EC 4.2.1.1) in metabolism is well-established, pharmacological applications of this phenomenon started to be considered only recently. In organisms all over the phylogenetic tree, the seven CA genetic families known to date are involved in biosynthetic processes and pH modulation, which may influence metabolism in multiple ways, with both processes being amenable to pharmacologic intervention. CA inhibitors possess antiobesity action directly by inhibiting lipogenesis, whereas the hypoxic tumor metabolism is highly controlled by the transmembrane isoforms CA IX and XII, which contribute to the acidic extracellular environment of tumors and supply bicarbonate for their high proliferation rates. Many of the articles from this special issue deal with the role of cancer CAs in tumor metabolism and how these phenomena can be used for designing innovative antitumor therapies/imaging agents. The metabolic roles of CAs in bacteria and algae are also discussed.

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Structure and function of carbonic anhydrases.

Claudiu Supuran (2016)

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyse the interconversion between CO2 and bicarbonate as well as other hydrolytic reactions. Among the six genetic families known to date, the α-, β-, γ-, δ-, ζ- and η-CAs, detailed kinetic and X-ray crystallographic studies have allowed a deep understanding of the structure-function relationship in this superfamily of proteins. A metal hydroxide nucleophilic species of the enzyme, and a unique active site architecture, with half of it hydrophilic and the opposing part hydrophobic, allow these enzymes to act as some of the most effective catalysts known in Nature. The CA activation and inhibition mechanisms are also known in detail, with a large number of new inhibitor classes being described in the last years. Apart from the zinc binders, some classes of inhibitors anchor to the metal ion coordinated nucleophile, others occlude the entrance of the active site cavity and more recently, compounds binding outside the active site were described. CA inhibition has therapeutic applications for drugs acting as diuretics, antiepileptics, antiglaucoma, antiobesity and antitumour agents. Targeting such enzymes from pathogens may lead to novel anti-infectives. Successful structure-based drug design campaigns allowed the discovery of highly isoform selective CA inhibitors (CAIs), which may lead to a new generation of drugs targeting these widespread enzymes. The use of CAs in CO2 capture processes for mitigating the global temperature rise has also been investigated more recently.

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How many carbonic anhydrase inhibition mechanisms exist?

Claudiu Supuran (2016)

Six genetic families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) were described to date. Inhibition of CAs has pharmacologic applications in the field of antiglaucoma, anticonvulsant, anticancer, and anti-infective agents. New classes of CA inhibitors (CAIs) were described in the last decade with enzyme inhibition mechanisms differing considerably from the classical inhibitors of the sulfonamide or anion type. Five different CA inhibition mechanisms are known: (i) the zinc binders coordinate to the catalytically crucial Zn(II) ion from the enzyme active site, with the metal in tetrahedral or trigonal bipyramidal geometries. Sulfonamides and their isosters, most anions, dithiocarbamates and their isosters, carboxylates, and hydroxamates bind in this way; (ii) inhibitors that anchor to the zinc-coordinated water molecule/hydroxide ion (phenols, carboxylates, polyamines, 2-thioxocoumarins, sulfocoumarins); (iii) inhibitors which occlude the entrance to the active site cavity (coumarins and their isosters), this binding site coinciding with that where CA activators bind; (iv) compounds which bind out of the active site cavity (a carboxylic acid derivative was seen to inhibit CA in this manner), and (v) compounds for which the inhibition mechanism is not known, among which the secondary/tertiary sulfonamides as well as imatinib/nilotinib are the most investigated examples. As CAIs are used clinically in many pathologies, with a sulfonamide inhibitor (SLC-0111) in Phase I clinical trials for the management of metastatic solid tumors, this review updates the recent findings in the field which may be useful for a structure-based drug design approach of more selective/potent modulators of the activity of these enzymes.

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Advances in structure-based drug discovery of carbonic anhydrase inhibitors.

Claudiu Supuran (2017)

The enzyme carbonic anhydrase (CA, EC 4.2.1.1) is found in numerous organisms across the tree of life, with seven distinct classes known to date. CA inhibition can be exploited for the treatment of edema, glaucoma, seizures, obesity, cancer and infectious diseases. A myriad of CA inhibitor (CAI) classes and inhibition mechanisms have been identified over the past decade, mainly through structure-based drug design approaches. Five different CA inhibition mechanisms are presently known. Areas covered: Recent advances in structure-based CAI design are reviewed, with periodic table-based organization of inhibitor classes. Expert opinion: Various structure-based drug design studies have led to deep understanding of factors governing tight binding and selectivity for the various isoforms. Carboxylic acids, phenols, polyamines, diols, borols, boronic acids, coumarins and sulfonamides represent successful stories which led to an anti-tumor sulfonamide in Phase I clinical trials (SLC-0111). For many inhibitor classes, no detailed crystallographic data are available. Detailed structural characterization of all CAI classes may lead to further advances in the field with potential therapeutic implications in the management of indications including neuropathic pain, cerebral ischemia, arthritis and tumor imaging.

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Journal

Journal ID (nlm-ta): Metabolites

Journal ID (iso-abbrev): Metabolites

Journal ID (publisher-id): metabolites

Title: Metabolites

Publisher: MDPI

ISSN (Electronic): 2218-1989

Publication date (Electronic): 21 March 2018

Publication date Collection: June 2018

Volume: 8

Issue: 2

Electronic Location Identifier: 25

Affiliations

Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche, Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, 50019 Florence, Italy; claudiu.supuran@ 123456unifi.it

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Claudiu T. Supuran https://orcid.org/0000-0003-4262-0323

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Publisher ID: metabolites-08-00025

DOI: 10.3390/metabo8020025

PMC ID: 6027401

PubMed ID: 29561812

SO-VID: 41660d67-a921-4125-a157-8578fa0ca491

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Carbonic Anhydrases and Metabolism

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Cancer Metabolism

Most cited references 39

Structure and function of carbonic anhydrases.

How many carbonic anhydrase inhibition mechanisms exist?

Advances in structure-based drug discovery of carbonic anhydrase inhibitors.

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