User:Cuine100/sandbox

Ferrochelatase is an enzyme that is encoded by the FECH gene in humans. Ferrochelatase catalyses the terminal (eighth) step in the biosynthesis of heme, converting protoporphyrin IX into heme B. It catalyses the reaction:
 * protoporphyrin + Fe+2 ↔ heme B + 2 H+



Function


Ferrochelatase catalyzes the insertion of ferrous iron into protoporphyrin IX in the heme biosynthesis pathway to form heme B. The enzyme is localized to the matrix-facing side of the inner mitochondrial membrane. Ferrochelatase is the best known member of a family of enzymes that add divalent metal cations to tetrapyrrole structures. For example, magnesium chelatase adds magnesium to protoporphyrin IX in the first step of bacteriochlorophyll biosynthesis.

Heme B is an essential cofactor in many proteins and enzymes. In particular, heme b plays a key role as the oxygen carrier in hemoglobin in red blood cells and myoglobin in muscle cells. Furthermore, heme B is found in cytochrome b, a key component in Q-cytochrome c oxidoreductase (complex III) in oxidative phosphorylation.

Structure
Human ferrochelatase is a homodimer composed of two 359 amino acid polypeptide chains. It has a total molecular weight of 85.07 kDa. Each subunit is composed of five regions: a mitochondrial localization sequence, the N terminal domain, two folded domains, and a C terminal extension. Residues 1-62 form a mitochondrial localization domain that is cleaved in post-translational modification. The folded domains contain a total of 17 α-helices and 8 β-sheets. The C terminal extension contains three of the four cysteine residues (Cys403, Cys406, Cys411) that coordinate the catalytic iron-sulfur cluster (2Fe-2S). The fourth coordinating cysteine resides in the N-terminal domain (Cys196).

The active pocket of ferrocheltase consists of two hydrophobic "lips" and a hydrophilic interior. The hydrophobic lips face the inner mitochondrial membrane and facilitate the passage of the poorly soluble protoporphyrin IX substrate and the heme product via the membrane.

Mechanism
The exact mechanism of human protoporphyrin metallation is not perfectly understood; nevertheless, data from other organisms provide some insight. Researchers studying Bacillus subtilis ferrochelatase propose a mechanism for iron insertion into protoporphyrin in which the enzyme tightly grips rings B, C, and D while bending ring A 36o. Normally planar, this distortion exposes the lone pair of electrons on the nitrogen in ring A to the Fe+2 ion. A highly conserved histidine residue (His183) is essential for the distortion, as well as metallation and possibly proton extraction. Subsequent investigation revealed a 100o distortion in protoporphyrin bound to human ferrochelatase.

Clinical significance
Defects in ferrochelatase create a buildup of protoporphyrin IX, causing erythropoietic protoporphyria (EPP). The disease can result from a variety of mutations in FECH, most of which behave in an autosomal dominant manner with low clinical penetrance. Clinically, patients with EPP present with a range of symptoms, from asymptomatic to suffering from an extremely painful photosensitivity. In less than five percent of cases, accumulation of protoporphyrin in the liver results in cholestasis (blockage of bile flow from the liver to the small intestine) and terminal liver failure.

Interactions
Ferrochelatase has been shown to interact with ABCB7.