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FRISC: The Faculty Research Interests Science Comparator |
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Assistant Professor of Internal Medicine, Division of Endocrinology and
Metabolism
Biological
Chemistry
Molecular Biophysics
Office: 214-648-6751
FAX: 214-648-8917
Email: richard.auchus@utsouthwestern.edu
Homepage: http://www.swmed.edu/home_pages/endocrine/auchusindex.htm
Protein Engineering, Genetics, Cellular Regulation, and Structural Biology of
Human Steroidogenesis
Human CYP17 performs both the 17 a -hydroxylase
and the 17, 20-lyase reactions in steroid biosynthesis, yet these two activities
are differentially regulated in human physiology in a developmentally-regulated
pattern. In particular, cytochrome b 5 selectively augments the
17,20-lyase activity of CYP17—which is necessary for sex steroid
biosynthesis—without significantly changing 17 a -hydroxylase
activity. We are studying the mechanism(s) that regulate the 17, 20-lyase
activity, particularly the biochemical basis of cytochrome b 5
stimulation. As part of this effort, we are constructing modified forms of
CYP17 designed to be more soluble and thus more suitable for biophysical
studies. In addition, we are characterizing the molecular genetics and
clinical manifestations of novel forms of CYP17 deficiencies that are either
partial or selective for only some activities of the enzyme, including the
characterization of a large Brazilian cohort with many heterozygous carriers.
Derivative from these studies, we are performing
structure-function studies on CYP17 and on a closely related enzyme, CYP21B
(21-hydroxylase). Using structural models derived from computational
chemistry to guide site-directed mutagenesis experiments, we are attempting to
engineer novel activities onto these enzymes. We hope that these studies
will illuminate the structural basis of the unique regiochemistries of these
related enzymes.
In an analogous protein engineering project, we have shown
that human hydroxysteroid dehydrogenase (HSD) enzymes, which are considered
unidirectional enzymes when expressed in cells, actually catalyze fully
reversible reactions in vivo . We wish to determine the structural
basis that dictates the apparent in vivo directionality (oxidative or
reductive) of human HSD enzymes as well as the physiological consequences of
their microscopic reversibility. We will also ask whether these enzymes
are modular in their construction and why the short-chain dehydrogenase/reductase
members of this family always function as dimers or oligomers.
On a cellular level, we are interested in the subcellular
localization of 3 b -hydroxysteroid dehydrogenase/ D 5-4 -isomerase (3 b HSD),
which irreversibly transforms D 5 steroids
to their D 4 congeners. We view the
subcellular localization of 3 b HSD as a potentially
regulated event that aids in determining the flux of steroids down the pathways
to mineralocorticoids, glucocorticoids, and sex steroid precursors.
Finally, some processes in human steroid biochemistry, such
as the formation of 17 a -hydroxysteroids like
epitestosterone and the metabolism of 5 a -reduced,
21-carbon steroids, remain to be elucidated. We would like to define these
pathways by isolating genes for these enzymes and by characterizing the
biochemistry and physiology of these novel pathways.
Selected Publications:
Geller DH, Auchus RJ, Mendonca BB, and Miller WL (1997) The
genetic and functional basis of isolated 17,20 lyase deficiency. Nature Genet
17:201-205.
Auchus RJ, Lee TC, and Miller WL (1998) Cytochrome b 5
augments the lyase activity of human P450c17 without direct electron transfer. J
Biol Chem 273:3158-3165.
Auchus RJ and Miller WL (1999) Molecular modeling of human
P450c17 (17 a -hydroxylase/17,20-lyase): insights into
reaction mechanisms and effects of mutations Mol Endocrinol 13:1169-1185.
Auchus RJ (2000) The Genetics, Pathophysiology, and
Management of Human Deficiencies of P450c17. Endocrinol Metab Clin NA
30:101-119.
Auchus RJ and Miller WL (2000) The principles, pathways, and
enzymes of human steroidogenesis. IN: Endocrinology , 4 th
edition, edited by L.J. DeGroot. Philadelphia: W.B. Saunders 115:1616-1631.
Arlt W, Auchus RJ, and Miller WL (2001) Thiazolidinediones
but not metformin directly inhibit the steroidogenic enzymes P450c17 and 3 b -hydroxysteroid
dehydrogenase. J Biol Chem 276:16767-16771.
Gupta MK, Geller DH, and Auchus RJ (2001) Pitfalls in
characterizing P450c17 mutations associated with isolated 17, 20-lyase
deficiency. J Clin Endocrinol Metab 86:4416-4423.
Extraction Method: Expand using Medical Synonyms-
Eliminated words list: MedlinePlus List
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Similarity Method: Weighted keyword count
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Database: Medline abstracts (1967 - Present)
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Publication Type: All
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Score Calculation Method: Cosine Similarity Method
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Sort by: Score
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Show: Top 100 hits
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Results computed on: 6/9/2006