Carbonic anhydrase XII functions in health and disease

Abstract

Human CAXII was initially identified as a cancer marker in different cancers and tumors. Expression of CAXII is regulated by hypoxia and estrogen receptors. CAXII expression has been also detected in several tissues, whereas in cancer and tumor tissues its expression is several fold higher. In brain tumors, an alternatively spliced form of CAXII is expressed. Higher expression of CAXII in breast cancer is indicative of lower grade disease. CAXII plays a key role in several physiological functions. Mutation in the CAXII gene causes cystic fibrosis-like syndrome and salt wasting disease. CAXII is also seen in nuclear pulposus cells of the vertebrae. Aging dependent stiffness or degeneration of backbone correlates with CAXII expression level. This finding suggests a possible implication of CAXII as a biomarker for chronic back pain and a pharmacological target for possible treatment of chronic back pain.

Keywords: Cystic fibrosis-like disease; Hyponatremia; Membrane-associated enzyme; Tumor marker.

Figure 1

Genomic organization of CAXII gene. A. The Homo sapiens gene contains 13 exons whereas the mouse gene (B) has 11 exons (38). Other mouse CA genes contain different numbers of exons; however, the functional domains are highly conserved (2). The amino acid sequences for Homo sapiens (Gene ID 771) and Mus musculus (Gene ID 76459) shown below were obtained from the Gene database in NCBI using the Ensembl Genome Browser (release 87).

Figure 2

Amino acid sequence homology of human carbonic anhydrases. Sequence homology alignment of human CAs show highly conserved residues among all enzymes. Conserved amino acids near the active site, including important histidine residues, are boxed. Metal binding histidine residues are marked by an arrow. Glycosylation sites are not conserved among all CAs and are indicated for CAXII by stars. Trans-membrane domains and phosphorylation sites are underlined (21), Copyright 1998.

Figure 3

Crystal structure of CAXII. Human carbonic anhydrase XII was crystallized at pH 7.5. Diffraction results of CAXII at 1.55 Å resolution suggested that the crystals belong to space group C2 with unit dimensions a=1.46.7 Å, b=44.6 Å, c=85.2 Å, and B=94.1 Å. One homodimer occupied the asymmetric unit. The native structure of CAXII consists of a dimer containing two zinc atoms, two Zn bound acetate ions, and 537 water molecules (9), Copyright 2001.