Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


THESIS REVISED FORMATTED.pdf (24.25 MB)

ETD Abstract Container

Abstract Header

Mechanisms Controlling Vitamin A Homeostasis in the Gut and Periphery

Kelly, Mary E, Kelly
http://rave.ohiolink.edu/etdc/view?acc_num=case1528476852462429

Abstract Details

2018, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
Vitamin A homeostasis control on different levels is essential to maintain retinoid function in peripheral tissues and to ensure optimal vision and requires a well-coordinated team of metabolic enzymes and transport proteins. The production of vitamin A from a chemically diverse set of over 60 putative provitamin A precursors poses a metabolic challenge. We scrutinized enzymatic properties of the two carotenoid cleavage dioxygenases (CCDs), BCO1 and BCO2, which catalyze the metabolism of carotenoids. Recombinant BCO1 split substrates at the C15,C15’ position adjacent to a canonical but not substituted ß-ionone ring site to vitamin A aldehyde, and was not impeded by removal of methyl groups from the substrate backbone. BCO2 split substrates at the C9,C10 position adjacent to assorted ionone ring sites. Kinetic analysis revealed a higher catalytic efficiency of BCO2 with substrates bearing non-canonical ionone rings. Accordingly b- cryptoxanthin, with one canonical and one non-canonical ionone ring site, was xix exclusively converted by both CCDs to retinoids in mice. Homology modeling and site directed mutagenesis identified amino acid residues at the entrance of the BCO1 substrate tunnel which determined its substrate specificity. Thus, selectivity of CCDs for distinct ionone ring sites guarantees production of vitamin A. To exert its effects, vitamin A must be distributed and transported across cell membranes, a process mediated by the STRA6 protein. Impaired vitamin A transport and homeostasis are associated with type 2 diabetes and Matthew Wood Syndrome. STRA6’s role in vitamin A homeostasis is defined. Stra6-/- mice were raised on diets sufficient or insufficient for vitamin A, with heterozygous sibling controls. Vitamin A levels of eyes, brain and testes, which highly express Stra6, as well as lung and fat, were measured, and consequences of STRA6 deficiency on retinoid-dependent processes were determined. Furthermore, effects of STRA6 deficiency on retinoid homeostasis of the aging mouse were determined. Thus STRA6 is critical for the transport of vitamin A over blood-tissue barriers. Fat and lung rely on dietary vitamin A. In testis and brain, Stra6 expression was regulated by vitamin A, reducing vitamin A consumption in controls when the dietary supply was limited, sequestering it for the eye.
Johannes von Lintig, PhD (Advisor)
Marcin Golczak, PhD (Committee Chair)
Timothy Kern, PhD (Committee Member)
Joseph LaManna, PhD (Committee Member)
Derek Taylor, PhD (Committee Member)
193 p.
Biochemistry; Pharmacology
Carotenoids; Provitamin A; STRA6; BCO1; BCO2

Recommended Citations

Citations

  • Kelly, Kelly, M. E. (2018). Mechanisms Controlling Vitamin A Homeostasis in the Gut and Periphery [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1528476852462429

    APA Style (7th edition)

  • Kelly, Kelly, Mary. Mechanisms Controlling Vitamin A Homeostasis in the Gut and Periphery. 2018. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1528476852462429.

    MLA Style (8th edition)

  • Kelly, Kelly, Mary. "Mechanisms Controlling Vitamin A Homeostasis in the Gut and Periphery." Doctoral dissertation, Case Western Reserve University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1528476852462429

    Chicago Manual of Style (17th edition)

case1528476852462429
200
© 2018, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.