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      Structure, dynamics and function of the evolutionarily changing biliverdin reductase B family.

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          Biliverdin reductase B (BLVRB) family members are general flavin reductases critical in maintaining cellular redox with recent findings revealing that BLVRB alone can dictate cellular fate. However, as opposed to most enzymes, the BLVRB family remains enigmatic with an evolutionarily changing active site and unknown structural and functional consequences. Here, we applied a multi-faceted approach that combines X-ray crystallography, NMR and kinetics methods to elucidate the structural and functional basis of the evolutionarily changing BLVRB active site. Using a panel of three BLVRB isoforms (human, lemur and hyrax) and multiple human BLVRB mutants, our studies reveal a novel evolutionary mechanism where coenzyme 'clamps' formed by arginine side chains at two co-evolving positions within the active site serve to slow coenzyme release (Positions 14 and 78). We find that coenzyme release is further slowed by the weaker binding substrate, resulting in relatively slow turnover numbers. However, different BLVRB active sites imposed by either evolution or mutagenesis exhibit a surprising inverse relationship between coenzyme release and substrate turnover that is independent of the faster chemical step of hydride transfer also measured here. Collectively, our studies have elucidated the role of the evolutionarily changing BLVRB active site that serves to modulate coenzyme release and has revealed that coenzyme release is coupled to substrate turnover.

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          Author and article information

          J Biochem
          Journal of biochemistry
          Oxford University Press (OUP)
          Aug 01 2020
          : 168
          : 2
          [1 ] Biochemistry & Cellular and Molecular Biology Department, University of Tennessee, 1311 Cumberland Ave., Knoxville, TN 37996, USA.
          [2 ] Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, 12801 E 17th Ave., Aurora, CO 80045, USA.
          [3 ] Molecular Biology Consortium, Advanced Light Source, Lawrence Berkeley National Laboratory, 1 Cyclotron Rd., Berkeley, CA 94720, USA.
          [4 ] Division of Medical Oncology, School of Medicine, University of Colorado, 12801 E 17th Ave., Aurora, CO 80045, USA.
          © The Author(s) 2020. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

          biliverdin reductase B,coenzyme,dynamics,enzyme
          biliverdin reductase B, coenzyme, dynamics, enzyme


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