Biochem - Norman, Anthony W.

Anthony W. Norman
Emeritus
Presidential Chair
Distinguished Professor of Biochemistry and Biomedical Sciences

Molecular Endocrinology
Signal Transduction
Biomedical Research
B.A., 1959 Oberlin College
Ph.D., 1963 Biochemistry, University of Wisconsin, Madison
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
Fellow, American Society of Nutrition, 2004

VOICE: 951-827-4777
FAX: 951-827-4784
MAIL: anthony.norman@ucr.edu

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, 1a,25(OH)₂-vitamin D₃ [1a,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 1a,25(OH)₂D₃ and 24R,25(OH)₂D₃. After systemic transport, 1a,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 [VDR_nuc] and rapid signal transduction pathways involving a membrane receptor [VDR_mem]. 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:

determination of the preferred molecular orientation of the conformationally mobile 1a,25(OH)₂D₃ as it forms a stable ligand-receptor complex with the ligand binding domain(s) of the VDR_nuc, VDR_mem, and the vitamin D-binding protein [DBP] (which is involved with transport of vitamin D and its metabolites in the blood compartment);
preparation of site-directed mutations in the VDRnuc so as to define the specific points of interaction between the receptor and the ligand [1a,25(OH)₂D₃ or analogs] that are essential for effective transactivation;
biochemical and mechanistic studies on the signal transduction pathways involved in rapid actions of 1a,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;
biochemical characterization of the VDR_mem associated with rapid responses
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, 1a,25(OH)₂-vitamin D₃ [1a,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 1a,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.

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" 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 D_3:

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)

Biochemistry Department

Faculty Information

Norman, Anthony W.

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