Individual Listing

5456 BOYCE HALL
University of California
Riverside, CA 92521

Norman, Anthony W

Distinguished Prof of Biochem & Biomedical Sci, Emeritus
Presidential Chair in Biochemistry-Emeritus

College of Natural and Agricultural Sciences

Biochemistry


Biography

 

Degrees

PhD. Biochemistry 1963

University of Wisconsin, Madison

MS Biochemistry 1961

University of Wisconsin, Madison

BA Chemistry 1959

Oberlin College

Awards

Postdoctoral, 1963/64 UCLA, Ernst Oppenheimer Award, 1977, The Endocrine Society
Mead Johnson Award, 1977, American Institute of Nutrition
Faculty Research Lecturer, 1982, UC-Riverside
Osborne and Mendel Award, 1990, American Institute of Nutrition
William F. Neuman Award, 1995, American Society of Bone & Mineral Research
Fellow, American Association Advancement Science, 1996


Research Area

The purpose of my research program is the investigation of the vitamin D endocrine system and the most biologically active steroid hormones derived from the parent vitamin D, 1,25(OH)2-vitamin D3 [1,25(OH)2D3] and 24R,25(OH)2-vitamin D3 [24R,25(OH)2D3]. The major thesis of our studies is that in terms of its chemical structure and mode of action, the seco-steroid, vitamin D (calciferol), is similar to other classic steroid hormones. The kidney is the endocrine gland that produces, in a physiologically regulated fashion, small amounts of 1,25(OH)2D3 and 24R,25(OH)2D3. After systemic transport, 1,25(OH)2D3 generates a wide array of biological responses (in over 30 target tissues) both by classical regulation of gene transcription via a nuclear receptor [VDRnuc] and rapid signal transduction pathways involving a membrane receptor [VDRmem]. The second hormone, 24R,25(OH)2D3, plays a subsidiary role in certain selected physiological circumstances, particularly in bone development and fracture-healing. Ongoing projects include the following: a. determination of the preferred molecular orientation of the conformationally mobile 1,25(OH)2D3 as it forms a stable ligand-receptor complex with the ligand binding domain(s) of the VDRnuc, VDRmem, and the vitamin D-binding protein [DBP] (which is involved with transport of vitamin D and its metabolites in the blood compartment); b. preparation of site-directed mutations in the VDRnuc so as to define the specific points of interaction between the receptor and the ligand [1,25(OH)2D3 or analogs] that are essential for effective transactivation; c. biochemical and mechanistic studies on the signal transduction pathways involved in rapid actions of 1,25(OH)2D3, including opening of chloride channels and activation of protein kinase C and MAP kinase, and "cross talk" from rapid responses to genomic responses; d. biochemical characterization of the VDRmem associated with rapid responses e. determination of the biological role of 24R,25(OH)2D3 in cartilage and bone during fracture-healing. • Henry / Norman Vitamin D Research Group Vitamin D Nuclear Receptor Three-dimensional model of the ligand binding domain (LBD) of the nuclear receptor (VDR) for the steroid hormone, 1,25(OH)2-vitamin D3 [1,25(OH)2D3], based on the atomic coordinates of the nuclear receptor for thyroid hormone. The left panel illustrates the twelve a-helices of the protein (presented as ribbons) and four b-strands that collectively define the LBD of the VDR. Each helix has its own unique color. The right panel depicts 1,25(OH)2D3 (blue colored molecule) beginning to enter the VDR LBD, which is a CP space-filling representation; the color-coding of the 12 helices of the VDR is the same as in the left panel

Publications

Selected Recent Publications (from a total of 750 publications) from the Laboratory of Anthony W. Norman:

Norman, A.W., H.L.Henry, J.E. Bishop, X-D. Song, C. Bula, and W.H. Okamura "Different shapes of the steroid hormone 1a,25(OH)2-vitamin D3 act as agonists for two different receptors in the vitamin D endocrine system to mediate genomic and rapid responses" Proceedings of First International Conference on Chemistry and Biology of Vitamin D Analogs, September 1999, Providence, RI. Steroids 66:147-158 (2001). (AWN-714.pdf)

Norman, A.W., Mizwicki, M.T., Norman, D.P.G. Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model. Nature Reviews: Drug Discovery 3:27-41 (2004). (AWN-748.pdf)

Zanello, L.P., and Norman, A.W. Rapid modulation of osteoblast ion channel responses by 1a,25(OH)2-vitamin D3 requires the presence of a functional vitamin D nuclear receptor. PNAS 101: 1589-1594 (2004). (AWN-751.pdf)

Mizwicki, M.T., Keidel, D., Bula, C.M., Bishop, J. E., Zanello, L.P., Wurtz, J.-M., Moras, D. and Norman, A.W. Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1a,25(OH)2-vitamin D3 signaling. PNAS 101:12876-12881 (2004). (AWN-759.pdf)

Huhtakangas, J.A., Olivera, C.J., Bishop, J.E., Zanello, L.P, and Norman, A.W. The vitamin D receptor is present in caveolae and binds 1a,25(OH)2-vitamin D3 in vivo and in vitro. Mol. Endo. 18:2660-2671 (2004). (AWN-761.pdf)

Vertino, A.M., Chen, J.-R., Kousteni, S., Han, L., Bellido, T., Bula, C.M., Norman, A.W., and Manolagas, S.C. Nongenotropic, anti-apoptotic signaling of vitamin D analogs through the ligand binding domain (LBD) of the vitamin D receptor (VDR) in osteoblasts and osteocytes: Mediation by Src, P13, and JNK kinases. J. Biol. Chem. 280:14130-14137 (2005). (AWN-763.pdf)

Bula, C.M., Huhtakangas, J.A., Olivera, C. J., Bishop, J.E., Norman, A.W., Henry, H.L. Presence of a Truncated Form of VDR in a Strain of VDR KO Mice. Endocrinology. 146:5581-5586 (2005). (AWN-769.pdf)

Norman, A.W. Vitamin D Receptor (VDR): New assignments for an already busy receptor. Endocrinology 147: 5542-5548 (2006). (AWN-771.pdf)

Vieth, R., Bischoff-Ferrari, H., Boucher, B., Dawson-Hughes, B., Garland, C., Heaney, R., Holick, M., Hollis, B., Lamberg-Allardt, C., McGrath, J., Norman, A., Scragg, R., Whiting, S., Willett, W., and Zittermann, A. The urgent need to recommend an intake of vitamin D that is effective. Am. J. Clin. Nutr. 2007 85: 649-650 (2007). (AWN-774.pdf)

Mizwicki, M., Bula, C., Bishop, J., Norman, A.W. New insights into vitamin D sterol-VDR proteolysis, allostery, structure-function from the perspective of a conformational ensemble model. Journal of Steroid Biochemistry & Molecular Biology 103: 243-262 (2007). (AWN-775.pdf)

Bula, C., Bishop, J., Norman A.W. Conservative mutageneic perturbations of amino acids connecting helix 12 in the 1a,25(OH)2-D3 receptor (VDR) to the ligan cause significant transactivational effects. Journal of Steroid Biochemistry & Molecular Biology. 103: 286-292 (2007). (AWN-776.pdf)

Historical Publications from the Norman Laboratory of Some Importance:

Discovery of the Steroid Hormone, 1,25(OH)2D3:

Haussler, M. R., J. F. Myrtle and A. W. Norman. The association of a metabolite of vitamin D3 with intestinal mucosa chromatin in vivo. J. Biol. Chem. 243, 4055-4064 (1968). [Note: This was the first publication to report the existence of 1a,25(OH)2D3 whose structure was subsequently reported in Science 173: 51-54 (1971).] (AWN-21.pdf)

Myrtle, J. F., M. R. Haussler and A. W. Norman. Evidence for the biologically active form of cholecalciferol in the intestine. J. Biol. Chem. 245, 1190-1196 (1970). [Note: This paper was subsequently selected as a "nutrition classic" by Nutrition Reviews, 49, 302-305 (1991) where it was republished.] (AWN-27.pdf)

Myrtle, J. F. and A. W. Norman. Vitamin D: a cholecalciferol metabolite highly active in promoting intestinal calcium transport. Science 171:78-82 (1971). (AWN-33.pdf)

Discovery of the Vitamin D Receptor (VDR) :

Haussler, M. R. and A. W. Norman. Chromosomal receptor for a vitamin D metabolite. Proc. Natl. Acad. Sci. USA 62, 155-162 (1969). [Note: This paper was subsequently selected as a "nutrition classic" by Nutrition Reviews, 43, 181-183 (1985) where it was republished.] (AWN-25.pdf)

Norman, A.W., D. Adams, E.D. Collins, W.H. Okamura and R.J. Fletterick. Three-dimensional model of the ligand binding domain of the nuclear receptor for 1a,25-dihydroxy-vitamin D3. Journal of Cellular Biochemistry 74:323-333 (1999). (AWN-693)

Treatment of first patients with the Steroid Hormone 1,25(OH)2vitamin D3:

Brickman, A. S., J. W. Coburn, A. W. Norman. Action of 1,25-dihydroxycholecalciferol, a potent, kidney-produced metabolite of vitamin D3, in uremic man. New Engl. J. Med. 287, 891-895 (1972).

Brickman, A. S., J. W. Coburn, K. Kurokawa, J. E. Bethune, H. E. Harrison and A. W. Norman. Actions of 1,25-dihydroxycholecalciferol in patients with hypophosphatemic vitamin D-resistant rickets. New Engl. J. Med. 289, 495-498 (1973).

Brickman, A. S., J. W. Coburn, S. G. Massry and A. W. Norman. 1,25-Dihydroxyvitamin D3 in normal man and patients with renal failure. Ann. Intern. Med. 80, 161-168 (1974).

Bar, A. and A. W. Norman. Studies on the mode of action of calciferol XXXIV. Relationship of the distribution of 25-hydroxyvitamin D3 metabolites to gonadal activity and egg shell formation in the quail. Endocrinology 109:950-955 (1981). (AWN-277)

Reichel, H., H. P. Koeffler and A. W. Norman. The role of the vitamin D endocrine system in health and disease. New England Journal of Medicine 320:980-991 (1989). (AWN-505)

Vitamin D and 1a,25(OH)2D3 are Important for Insulin Secretion:

Norman, A.W., B.J. Frankel, A M. Heldt and G.M. Grodsky. Vitamin D deficiency inhibits pancreatic secretion of insulin. Science 209:823-825 (1980). (AWN-244)

Christakos, S. and A. W. Norman. Studies on the mode of action of calciferol XXIX. Biochemical characterization of 1,25-dihydroxyvitamin D3 receptors in chick pancreas and kidney cytosol. Endocrinology 108:140-149 (1981). (AWN-265)
Roth, J., S. Bonner-Weir, A. W. Norman and L. Orci. Immunocytochemistry of vitamin D dependent calcium binding protein in chick pancreas: Exclusive localization in b-cells. Endocrinology 111:2216-2218 (1982). (AWN-297)

Kadowaki, S. and A. W. Norman. Studies on the mode of action of calciferol. XLIX. Dietary vitamin D is essential for normal insulin secretion from the perfused rat pancreas. Journal of Clinical Investment 73:759-766 (1984). (AWN-357)
Kadowaki, S. and A. W. Norman. Demonstration that the vitamin D metabolite 1,25(OH)2-vitamin D3 and not 24R,25(OH)2-vitamin D3 is essential for normal insulin secretion in the perfused rat pancreas. Diabetes 34:315-320 (1985). (AWN-387)

Kadowaki, S. and A.W. Norman. Studies on the mode of action of calciferol. LIX. Time course study of the insulin secretion after 1,25-dihydroxyvitamin D administration. Endocrinology 117:1765-1771 (1985). (AWN-414)
1,25(OH)2D3 Mediates Rapid Biological Responses:

Nemere, I., Y. Yoshimoto and A. W. Norman. Studies on the mode of action ofcalciferol. LIV. Calcium transport in perfused duodena from normal chicks: Enhancement within14 minutes of exposure to 1,25-dihydroxyvitamin D3. Endocrinology 115:1476-1483 (1984). (AWN-376.pdf)
Nemere, I. and A.W. Norman. Studies on the mode of action of calciferol LII. Rapid action of 1,25-dihydroxyvitamin D3 on calcium transport in perfused chick duodenum: Effect of inhibitors. Journal of Bone and Mineral Research 2:99-107 (1987). (AWN-445)

Nemere, I. and A.W. Norman. 1,25-Dihydroxyvitamin D3-mediated vesicular transport of calcium in intestine: Time course studies. Endocrinology 122:2962-2969 (1988). (AWN-478)
Nemere, I., V. L. Leathers, B. S. Thompson, R. A. Luben and A. W. Norman. Redistribution of Calbindin -D28K in Chick Intestine in Response to Calcium Transport. Endocrinology 129/6 2972-2984 (1991). (AWN-553.pdf)

Norman, A.W., R. Bouillon, M.C. Farach-Carson, J.E. Bishop, L-X. Zhou, I. Nemere, J. Zhao, K.R. Muralidharan, and W.H. Okamura. Demonstration that 1b,25-dihydroxyvitamin D3 is an antagonist of the nongenomic but not genomic biological responses and biological profile of the three A-ring diastereoisomers of 1a,25-dihydroxyvitamin D3. Journal of Biological Chemistry 268/27:20022-20030 (1993). (AWN-602.pdf)
Zanello, L.P. and A.W. Norman. Stimulation by 1a,25(OH)2-vitamin D3 of whole cell chloride currents in osteoblastic ROS 17/2.8 cells: A structure-function study. Journal of Biological Chemistry 272:22617-22622 (1997). (AWN-660.pdf)

Norman, A.W., W.H. Okamura, M.W. Hammond, J.E. Bishop, M.C. Dormanen, R. Bouillon, H. van Baelen, A.L. Ridall, E. Daane, R. Khoury, and M.C. Farach-Carson. Comparison of 6-s-cis- and 6-s-trans-locked analogs of 1a,25 dihydroxyvitamin D3 indicates that the 6-s-cis conformation is preferred for rapid nongenomic biological responses and that neither 6-s-cis- nor 6-s-trans-locked analogs are preferred for genomic biological responses. Molecular Endocrinology 11:1518-1531 (1997). (AWN-657.pdf)
Zanello, L.P., and Norman, A.W. Rapid modulation of osteoblast ion channel responses by 1a,25(OH)2-vitamin D3 requires the presence of a functional vitamin D nuclear receptor. PNAS 101: 1589-1594 (2004). (AWN-751.pdf )