Carbonic anhydrase-related proteins VIII, X, and XI: Evolutionary divergence and emerging biological roles

Carbonic anhydrases (CAs) constitute a large family of zinc metalloenzymes best known for catalyzing the reversible hydration of carbon dioxide. Within this family, three isoforms-carbonic anhydrase-related proteins (CARPs) VIII, X, and XI-are unusual because they lack catalytic activity due to substitutions in three histidine residues required for coordination of the catalytic Zn²⁺ ion. Despite the absence of enzymatic activity, these proteins are evolutionarily conserved and show distinct expression patterns, particularly in the central nervous system and reproductive tissues, suggesting biological functions beyond catalysis. Among the CARPs, CA VIII is the best characterized and has been associated with cerebellar development and motor coordination. Mutations in the CA8 gene are associated with neurological disorders, including cerebellar ataxia. In contrast, the functions of CA X and CA XI remain less well defined, although available evidence suggests their involvement in neuronal signaling and related regulatory processes. Previous reviews have summarized the current knowledge on CARPs. In this chapter, we provide an updated overview of their evolutionary divergence, expression patterns, molecular interactions, and biological roles. Particular attention is given to insights from genetic studies and model organisms. Despite increasing interest, several aspects of CARP biology remain incompletely understood, and further studies are required to clarify their physiological and pathological significance.