Carbonic anhydrases (CA) are a group of metalloenzymes that catalyze reversible hydration of carbon dioxide to bicarbonate. Isoforms of CA play a vital role in various processes including lipogenesis, glyconeogenesis, pH, and CO2 homeostasis. In this work, an isoform IX was studied by the means of theoretical methods. This isoform is over-expressed in solid tumors as a response to hypoxia conditions caused by insufficient supply of oxygen due to a massive tumor growth. CA IX helps to keep intracellular pH to a physiological level, but at the same time, it significantly lowers extracellular pH, which results in a higher risk of tumor cell invasiveness. CA IX is therefore a negative marker for people suffering from a cancer [1].
CA IX consists of proteoglycan domain (PG), catalytic domain (CA), transmembrane helix and intracytoplasmatic portion. The catalytic domain has a globular shape and accommodates a conical cavity where the active site is located [2]. The PG domain is a unique structural element to the isoform IX. It is assumed that it is a key to the excellent catalytic properties of CA IX. Despite numerous experimental efforts, the structure and exact function of the PG domain is not known. We employed molecular dynamics simulations to reveal its structure and function. Several constructs were simulated on ms time scales including the PG domain alone and constructs including both the CA and PG domains. Results indicate that the PG domain is rather unstructured portion of CA IX.
The work was done at CEITEC - Central European Institute of Technology with research infrastructure supported by the project CZ.1.05/1.1.00/02.0068 financed from European Regional Development Fund. The access to the MetaCentrum and CERIT-SC computing and storage facilities provided under the program "Projects of Large Infrastructure for Research, Development, and Innovations" LM2010005 funded by the Ministry of Education, Youth, and Sports of the Czech Republic and the programme Center CERIT Scientific Cloud, part of the Operational Program Research and Development for Innovations, reg. no. CZ. 1.05/3.2.00/08.0144 is acknowledged.