Carbonic anhydrases and PET

Carbonic anhydrases (CAs) are a family of zinc metalloenzymes that catalyse the reversible hydration of carbon dioxide to bicarbonate and a proton in a two-step reaction:

The reaction with water, involved in rapid CO2 transport and pH regulation,

is the best known function of carbonic anhydrases, and the basis of using [15O]CO2 in perfusion PET imaging. Carbonic anhydrase enzymes may catalyse also other hydration reactions (Aggarwal et al., 2013), such as

At least 12 catalytic and 3 acatalytic isoforms of human α-Ca are known. Their structure is very similar, but differ in expression and distribution: hCA-I is found in erythrocytes and GI tract; hCA-II in erythrocytes, GI tract, eyes, osteoclasts, kidneys, lungs, testes, and brain; hCA-III in skeletal muscle and adipocytes; hCA-IV in kidneys, lungs pancreas, brain, blood capillaries, colon, and heart muscle; hCA-VA in mitochondria of liver, and hCA-VB in mitochondria of heart and skeletal muscles, pancreas, kidneys, GI tract and spinal cord; hCA-VI is a secretory protein found in salivary and mammary glands; hCA-VII in central nervous system (CNS); acatalytic hCA-RP-VIII also in CNS; hCA-IX in tumours and GI mucosa; acatalytic hCA-RP-X and hCA-RP-XI in CNS; hCA-XII in renal, intestinal, and reproductive epithelia, eyes, and tumours; hCA-XIII in kidneys, brain, lungs, gut, and reproductive tract; and hCA-XIV in kidneys, brain, and liver. The hCA-I, hCA-II, hCA-III, hCA-VII, hCA-RP-VIII, hCA-RP-X, hCA-RP-XI, and hCA-XIII are found in cytosol; hCA-IV is membrane-bound; and hCA-IX, hCA-XII, and hCA-XIV are transmembrane proteins (Aggarwal et al., 2013).

Carbonic anhydrases in tumours

The transmembrane isoforms CA-IX and CA-XII have been shown to associated with tumours. CAs promote cancer cell survival by facilitating the transport of bicarbonate ions into the cell to maintain pH homeostasis during active glycolysis and hypoxia. Hypoxia-inducible factors 1/2 regulate the expression of CA-IX, which is a well-established surrogate marker for hypoxia (Lau et al., 2016). CA-IX is more prevalent in solid tumours than CA-XII, and therefore Ca-IX is considered as a therapeutic target and imaging marker for aggressive cancers (Mahon et al., 2014). Several PET radioligands targeting CA-IX have been developed (Lau et al., 2015 and 2016; Iikuni et al., 2020; Zhu et al., 2023).


See also:


Literature

Aggarwal M, Boone CD, Kondeti B, McKenna R. Structural annotation of human carbonic anhydrases. J Enzyme Inhib Med Chem. 2013; 28(2): 267-277. doi: 10.3109/14756366.2012.737323.



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Updated at: 2023-08-01
Created at: 2023-08-01
Written by: Vesa Oikonen