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Understanding Carotenoid and Retinoid Biochemical Diversity using Novel Archaeal and Eukaryotic Model Systems

Daruwalla, Anahita
http://rave.ohiolink.edu/etdc/view?acc_num=case1626709424672807

Abstract Details

2021, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
Carotenoid cleaving dioxygenases (CCD) are a group of proteins involved in oxidative cleavage of carotenoids and non-carotenoids using a non-heme iron center. Previous studies on structure and function of CCD in plants, cyanobacteria as well animals show these are typically regio- and stereo-specific for substrate cleavage. Some are also known to show double bond isomerization similar to the visual cycle isomerase RPE65. However, it is still unclear as to how certain members of this family evolved to function distinctly. More so, dearth of knowledge on CCDs in archaea makes it implausible to link their evolutionary divergence. Recent phylogenetic studies propose that eukaryotes have emerged from archaea, favoring a two-domain tree of life model with Archaea and Bacteria. Probing into the cleavage mechanism of CCDs in archaea would provide valuable insight into the evolution of these proteins. In an attempt to bridge this gap, we characterized a putative oxygenase from an archaeon, Candidatus Nitrosotalea devanaterra (NdCCD), with a close evolutionary relationship to metazoan CCDs. The structure of NdCCCD in complex with its apocarotenoid product displays similarity to RPE65 and helps discern the active site determinants for cleavage. RDH5, an 11-cis-retinol dehydrogenase present in the retinal pigment epithelium (RPE) of the eye retina catalyzes oxidation of 11-cis-retinol to 11- retinaldehyde, thus regenerating the visual chromophore. In humans, mutations in RDH5 are predominantly associated with fundus albipunctatus, characterized by presence of white flecks in the retina and delayed rod adaptation impairing night vision. However, a subset of patients also develops macular atrophy or cone dystrophy. Rdh5-/- mice do not recapitulate human phenotype and exhibit delayed dark adaptation only after prolonged bleaching. We characterized a new domestic cat model with a loss of function missense mutation in RDH5 that results in atrophy of its area centralis region (equivalent to the human macula). As in human patients, not all cats developed atrophy in their central retina, displaying phenotypic variability. This novel cat model provides opportunities to improve molecular understanding of macular degeneration and test therapeutic interventions for RDH5-associated retinopathies seen in humans.
Philip Kiser (Advisor)
Jason Mears (Committee Chair)
Johannes Von Lintig (Committee Member)
Youwei Zhang (Committee Member)
Paul Park (Committee Member)
Animal Diseases; Biochemistry; Molecular Biology

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Citations

  • Daruwalla, A. (2021). Understanding Carotenoid and Retinoid Biochemical Diversity using Novel Archaeal and Eukaryotic Model Systems [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1626709424672807

    APA Style (7th edition)

  • Daruwalla, Anahita. Understanding Carotenoid and Retinoid Biochemical Diversity using Novel Archaeal and Eukaryotic Model Systems . 2021. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1626709424672807.

    MLA Style (8th edition)

  • Daruwalla, Anahita. "Understanding Carotenoid and Retinoid Biochemical Diversity using Novel Archaeal and Eukaryotic Model Systems ." Doctoral dissertation, Case Western Reserve University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1626709424672807

    Chicago Manual of Style (17th edition)

case1626709424672807
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© 2021, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.