Carbonic anhydrases as disease markers

ABSTRACT

Introduction: The physiologic importance of fast CO₂/HCO₃⁻ interconversion in various tissues requires the presence of carbonic anhydrase (CA, EC 4.2.1.1). Fourteen CA isozymes are present in humans, all of them being used as biomarkers.

Area covered: A great number of patents and articles were focused on the use of CA isozymes as biomarkers for various diseases and syndromes in the recent years, in an ascending trend over the last decade. The review highlights the most important studies related with each isozyme and covers the most recent patent literature.

Expert opinion: The CAs biomarker research area expanded significantly in recent years, shifting from the predominant use of CA IX and CA XII in cancer diagnostic, staging, and prognosis towards a wider use of CA isozymes as disease biomarkers. CA isozymes are currently used either alone, in tandem with other CA isozymes and/or in combination with other proteins for the detection, staging, and prognosis of a huge repertoire of human dysfunctions and diseases, ranging from mild transformation of the normal tissues to extreme shifts in tissue organization and function. The techniques used for their detection/quantitation and the state-of-the-art in each clinical application are presented through relevant clinical examples and corresponding statistical data.

KEYWORDS:

• Carbonic anhydrases
• biomarker
• physiology
• pathology

Article highlights

• Isoforms of CA evolved to perform the efficient equilibration of CO₂/HCO₃⁻ in different environments. The normal biodistribution of all 14 CA isozymes is presented in detail, together with kinetic parameters, biochemical and physiologic details relevant for their activity.

• All CA isozymes are currently used as biomarkers, either alone, in combination with other CA isozymes, or as part of more complex biomarker sets.

• For each CA isozyme, we are revealing significant biodistribution differences that appear between normal and diseased states, which constitute the base for their use as biomarkers. The use of CA biomarkers expanded dramatically in recent years from cancer diagnostic, staging and prognosis to a wide repertoire of human dysfunctions and diseases.

• Relevant statistical data acquired in human subjects or in animal models of human diseases were compiled and presented for each CA isozyme from patent and literature data whenever possible, revealing the ability of each protein to discern between related pathologies or stages of a given disease. It allows one to evaluate the intrinsic quality of each CA biomarker and the limitations of its use. The correlation between the CA biomarker level and patient prognosis was also presented for a plethora of diseases in which CAs are involved, with statistical details.

• All methods currently available to detect/quantify CA isozymes were compiled from the newest patents and from relevant publications available for each isozyme. Besides traditional antibody-based detection/quantitation methods and RT-PCR, one can observe the recent widespread use of mass spectrometry-based techniques and chip-based screening technologies, including their state-of-the-art versions, presented for each CA biomarker/disease case.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the National Institutes of Health (R03EB026189) and the Temple University School of Pharmacy Drug Discovery Program. A Shabana and UK Mondal would like to thank TU Graduate School for a Dissertation Completion Grant.