Augmenter of liver regeneration: a flavin-dependent sulfhydryl oxidase with cytochrome creductase activity

Date
2013
Authors
Farrell, Scott
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Publisher
University of Delaware
Abstract
Augmenter of Liver Regeneration (ALR; hepatopoietin) has been studied as a flavin-linked sulfhydryl oxidase. Several lines of evidence suggest that human ALR is a disulfide-bridged dimer (linked via C15-C124) with two free cysteine residues (C74 and 85) per monomer. Here I will show that the C15-C124disulfides are not critical for dimer formation and have insignificant impact on the dithiothreitol (DTT) oxidase activity of ALR. Although the crystal structure of rat ALR shows a proximal disulfide (C62-C65) poised to interact with the FAD prosthetic group [Wu, C. K., Dailey, T. A., Dailey, H. A., Wang, B. C., and Rose, J. P. (2003) Protein Sci. 12, 1109-18] only flavin reduction is evident during redox titrations of the enzyme. ALR forms large amounts of the neutral flavosemiquinone during aerobic turnover with DTT. This semiquinone arises, in part, by comproportionation between flavin centers within the dimer. Surprisingly cytochrome c is about a 100-fold better electron acceptor for ALR than oxygen when DTT is the reducing substrate. Herein we discuss that this poorly understood flavoenzyme may not function as a sulfhydryl oxidase within the mitochondrial intermembrane space, but may communicate with the respiratory chain via the mediation of cytochrome c.
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