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Introduction

1f2w is a protein from the Carbonic anhydrase II (gene name CA2) sub-sub-family, which is one of the fourteen isoforms of human α carbonic anhydrases.

This enzyme is a lyase, which is able to break C-N links, and needs its cofactor, the zinc ion, to be activated.

Carbonic anhydrase II is located in the cytosol, and normally catalyzes the reversible hydration of CO2 into bicarbonate.

The 1f2w protein catalyzes reversible hydration of cyanamide into urea, which is an inhibitor of the carbonic anhydrase.

Structure

The carbonic anhydrase II is composed of 259 amino acids, and its dimensions are 42Å x 42Å x 72Å.

The protein is composed of :

- 5

- 15

The protein's active site is formed of (residues 94,96 and 119) that can bind a zinc ion. The active site is located in an hydrophobic hole :

Image:125.png

There is two binding sites for mercury :

- .

- .

We can see here the conservation of the residues:

The most conserved residues are located in the active site's cavity.

Function

1f2w catalyzes the hydration of cyanamide into urea according to the equation :

Cyanamide is a toxic compound, and is an analog of CO2. It can thereby bind the active site of the carbonic anhydrase.

The reaction is a suicide inhibition: the enzyme binds an suicide substrate (here cyanamide), and this substrate is modified by the enzyme (here into urea) and produces a reactive group that forms a stable inhibitor-enzyme complex.

Mechanism of Action

The can bind the metal ion and two threonine residues (THR 199 and 200), it is thereby adding to the coordination sphere. The cyanamid attacks the zinc ion (nucleophilic attack). Afertwards the water molecule performs a nucleophilic attack on the zinc-activated cyanamide substrate forming urea which remains bound to the metal.

Urea is tightly linked to the carbonic anhydrase II, acting in this way as an inhibitor.

Disease

Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:259730]; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.[1] [2] [3] [4] [5]