Heterocyclic periphery in the design of carbonic anhydrase inhibitors: 1,2,4-Oxadiazol-5-yl benzenesulfonamides as potent and selective inhibitors of cytosolic h CA II and membrane-bound h CA IX isoforms

Several carbonic anhydrase (CA) isoforms are associated with plasma membranes. It is probable that these enzymes interact with anion transporters to facilitate the movement of HCO3− into or out of the cell. A better knowledge of CA isoform expression in a given tissue would facilitate a systematic examination of any associations with such transporters. We examined the expression of CAs IV, IX, XII, and XIV mRNAs in rabbit tissues, including kidney, heart, lung, skeletal muscle, liver, pancreas, gall bladder, stomach, small intestine, colon, and spleen, using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). CA IV mRNA was mainly in kidney, heart, lung, colon, and gall bladder. CA IX mRNA was restricted to stomach, gall bladder, duodenum, and early jejunum. CA XII mRNA was found in kidney and colon. CA XIV mRNA was localized to heart, lung, skeletal muscle, and liver. The data indicate that there are different patterns of CA expression in various tissues: CA IX was expressed in the proximal gastrointestinal tract, whereas CA XII and CA IV were more distal. CA IV and CA XII are important kidney isoforms. CA XIV was abundant in metabolically active tissues such as liver, heart, lung, and skeletal muscle. Some significant species differences were noted in the expression of some of these isoforms; for example, CA XIV is not expressed in rabbit kidney, despite being abundant in mouse kidney. Maturational studies showed that the expression of CA IX mRNA and protein increased markedly with weaning (∼3–4 postnatal wk) and was well correlated with the maturational expression of the α-subunit of the gastric H+,K+-ATPase, suggesting that function of CA IX and the gastric H+ pump might be linked in the digestion of adult foodstuffs. The unique pattern of membrane-bound CA isoforms suggests different functional associations with transporters, depending on the physiological demands on the tissue.

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Structure of the carbonic anhydrase VI (CA6) gene: evidence for two distinct groups within the α-CA gene family

Biochemical Journal ◽

10.1042/bj3440385 ◽

1999 ◽

Vol 344 (2) ◽

pp. 385-390 ◽

Cited By ~ 8

Author(s):

Weiping JIANG ◽

Dwijendra GUPTA

Keyword(s):

Carbonic Anhydrase ◽

Untranslated Region ◽

Sequence Similarity ◽

Ca Ix ◽

Its Gene ◽

Exon 1 ◽

Membrane Bound ◽

Mature Enzyme ◽

Gene Structures ◽

Carbonic Anhydrase Vi

The secreted carbonic anhydrase (CA VI) is believed to be one of the oldest mammalian CAs in evolutionary terms. To elucidate its gene structure and compare it with other members of the α-CA family, we cloned genomic fragments encoding the bovine CA6 gene and determined its exon/intron organization. The gene spans approx. 25 kb and consists of eight exons and seven introns. Exon 1 encodes the 5′ untranslated region, the signal peptide and the N-terminus of the mature enzyme. Exon 8 encodes the 3′ untranslated region and the C-terminal extension that is unique to CA VI. Exons 2-7 encode the CA domain, which shows significant sequence similarity to other CAs. Two distinct groups exist in the α-CA family on the basis of a comparison of the known gene structures. One group consists of the cytoplasmic (CA I, II, III and VII) and mitochondrial (CA V) members. The other group consists of the membrane-bound (CA IV and IX) and secreted (CA VI) members. In particular, the seven exon/intron boundaries in the CA domain of the CA6 gene are conserved in the CA9 gene, which encodes the multidomain protein CA IX that is overexpressed in tumours and has transforming potential.

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