Japanese Researchers Illuminate Enzymatic Process That Produces Bilirubin, the Anti-Oxidant Molecule That, in Excess, Is Associated with Jaundice

Jaundice, marked by yellowing of the skin, is common in infants, but is also a symptom of various adult diseases. This discoloration is caused by excess bilirubin (BR), the substance that gives bile its yellow tinge. However, BR is also a vital antioxidant, which at healthy levels protects cells against peroxide damage. Its production in the body, though, has long been a source of uncertainty. Now, a Japanese research collaboration involving Osaka University and other Japan institutions believes it has the answer. BR is already known to be produced from a related chemical, biliverdin (BV), by the enzyme biliverdin reductase (BVR). The enzyme wraps around BV and transfers two hydrogen atoms – one positive and one negative – to produce the yellow antioxidant. However, biologists could not establish which part of the enzyme was chemically involved in the process (the active site), or where the positive hydrogen came from. The new findings, revealing this information, were published online on February 7, 2017 in Nature Communications. The open-access article is titled “A Substrate-Bound Structure of Cyanobacterial Biliverdin Reductase Identifies Stacked Substrates As Critical for Activity.” “Previous studies used BVR from rats, and could never crystallize the enzyme well enough to determine how it binds to BV,” study co-author Keiichi Fukuyama, Ph.D., says. “We realized that the same enzyme in Synechocystis bacteria had an almost identical fold-shape, but was easier to examine by X-ray crystallography.” To their surprise, the researchers found two molecules of BV – one stacked upon the other – at the active site, even though only one is converted to BR. From the X-ray data, they deduced why two were needed.
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