Israel Hanukoglu

Israel Hanukoglu
Born Istanbul, Turkey
Nationality Israeli
Fields Biochemistry, molecular biology
Institutions Ariel University
Alma mater Hebrew University of Jerusalem
Thesis Mechanism of electron transport to cytochrome P-450 in adrenal cortex mitochondrial monooxygenase systems (1980)
Doctoral advisor Colin Jefcoate
Other academic advisors Neal L. First, David Nelson, W.W. Cleland
Known for Keratin structure, steroidogenic enzymes, Epithelial sodium channels
Notable awards Lindner Prize

Israel Hanukoglu (Turkish: İsrael Hanukoğlu) is a Turkish-born Israeli scientist. He is a full professor of biochemistry and molecular biology[1] at Ariel University and former Science and Technology Adviser to the Prime Minister of Israel (1996–1999). He is founder of Israel Science and Technology Homepage.[2]

Education

Israel Hanukoglu received his undergraduate degree cum laude with double majors in biology and psychology and a minor in political science from the Hebrew University of Jerusalem. He then went to the University of Wisconsin-Madison for graduate studies and received his M.Sc. degree in 1976 in an inter-disciplinary Endocrinology-Reproductive physiology program. His Ph.D. thesis was on the "Mechanism of electron transport to cytochrome P-450 in adrenal cortex mitochondrial steroid monooxygenase systems" carried out under the supervision of Prof. Colin R. Jefcoate.

Contributions to science

Prof. Hanukoglu's scientific work concentrated in three different areas outlined below.

Structures of keratins

Hanukoglu's career in molecular biology started at the Department of Biochemistry of the University of Chicago (1980-1983 with Elaine Fuchs), where he cloned and sequenced cDNAs coding for cytoskeletal proteins, actin[3] and alpha keratins.[4][5] He elucidated the first structures of cytoskeletal keratin families, and predicted the long helical domains of these proteins. By computerized analysis of amino acid sequences he predicted that the central rod domain of intermediate filament proteins is composed of four helical segments separated by three short linker sequences. Later crystallographic studies have confirmed this as a general model for intermediate filament protein structure.[6][7]

Steroid hormone synthesis

During his Ph.D. thesis research, Israel isolated the mitochondrial enzymes that catalyze the first step in the synthesis of steroid hormones in all steroidogenic tissues, including the adrenal cortex, and the reproductive organs.[8] The first step of steroidogenesis is dependent on the transfer of electrons from NADPH to a P450 type enzyme (P450scc) via an electron-transfer chain that includes two additional proteins.[9] These proteins are located on the inner mitochondrial membrane.[10] Israel reconstituted this system using proteins he purified, characterized the process of electron transfer between the proteins, and built a kinetic model that simulated precisely the dynamic behavior of this complex system.[11][8]

In his first academic position at the Department of Biology at the Technion-Israel Institute of Technology, he first determined the molar stoichiometry of the mitochondrial P450 system proteins using specific antibodies that he generated.[12] He then set out to clone the cDNAs and the genes that code for these enzymes. His lab was the first to clone the cDNAs and the gene coding for adrenodoxin reductase - the first enzyme in the electron transfer chain of the mitochondrial P450 system.[13][14][15]

By sequence and structural analyses of adrenodoxin reductase, Israel identified its binding sites for the electron donor and acceptor coenzymes, NADPH and FAD.[14] By sequence analyses of the large oxidoreductase type of enzyme families, he noted that the FAD binding site is a classical Rossmann fold, but the NADPH binding site has a different consensus sequence that could be responsible for NAD vs. NADP coenzyme specificity. The importance of the motifs he identified was confirmed by re-engineering of coenzyme specificities of different enzymes.[16] Elucidation of the crystal structure of adrenodoxin reductase further verified Israel's identification of the coenzyme binding sites.[17]

As the steroidogenic tissues have very high levels of antioxidants, Israel suspected that the P450 systems may leak electrons producing oxygen radicals. He examined this issue and showed that indeed, electrons that leak during the action mitochondrial P450 systems generate reactive oxygen species.[18][19][20] His studies also showed that in bovine ovary, levels of antioxidants are coordinately regulated with steroidogenesis.[21]

His other work in this field includes elucidation of the mechanism of action of corticotropin (ACTH) in regulating steroid hormone synthesis in the adrenal cortex,[22][23] regulation of adrenal steroidogenic capacity in disease states,[24] and the cloning and elucidation of the structure of ACTH receptor.[25]

In this field, Israel organized the first International Symposium in Molecular Steroidogenesis in Jerusalem in 1991 which served as the cornerstone for a continuing series of international symposia for scientists who specialize in this field.[26]

Epithelial sodium channel (ENaC)

In his clinical work as an endocrinologist, Israel's senior brother, Prof. Aaron Hanukoglu (Tel Aviv University, Sackler Medical School and E. Wolfson Medical Center), identified that a hereditary disease named pseudohypoaldosteronism type I encompasses two independent syndromes.[27] Following this discovery the two brothers continued their collaboration to understand the molecular basis of the severe form of PHA.

By their collaborative work that also included additional labs, the Hanukoglu brothers discovered that the severe forms of pseudohypoaldosteronism type I result from mutations in three genes (SCNN1A, SCNN1B, and SCNN1B) that encode for protein subunits of the Epithelial sodium (Na+) channel (ENaC).[28][29][30][31] These studies also helped establish that ENaC is the principal channel involved in blood volume and blood pressure regulation in humans.[32]

Following these studies, the Hanukoglu brothers directed their attention to understand the structure and function of ENaC assembled from normal and mutated subunits. Their analyses showed that the phenotypic variations in the severity of pseudohypoaldosteronism are associated with the types of genetic mutations.[33][34] Their work on the structure of ENaC subunits led to the identification of charged residues and regions responsible for transport of the protein to membrane and for regulation of extracellular Na+ ions.[35][36]

In an extensive review of studies on ASIC and ENaC, Prof. Hanukoglu has summarized the major similarities between ASIC and ENaC type channels.[37]

To define the sites of localization of ENaC in tissues and within cells, Hanukoglu's laboratory generated polyclonal antibodies against extracellular ENaC subunits. These antibodies for the first time permitted visualization of intracellular localization of ENaC at high resolution and led to the discovery that in all cells with motile cilia ENaC is located on cilia.[38] These studies establish that ENaC is an important regulator of fluid level in the luminal side of cells with motile cilia in the reproductive and respiratory tract.[38]

Awards

In addition to the personal prizes above, the research presentations from the laboratory of Prof. Hanukoglu received four awards at national and international meetings.

Academic and Civic activities

Besides a scientific career Hanukoglu has maintained an active academic and civic leadership role. In 2003, Hanukoglu founded Israel's first Molecular Biology B.Sc. degree program in the Ariel University Center of Samaria[39] and served as the Chairman of the Molecular Biology Department there from 2003 to 2008.[40]

Prof. Hanukoglu is currently on the editorial board of three journals.[41] He is one of the top reviewers of scientific articles in the life sciences (ranked to be in the top 98 percentile according to the Publons registry).

In 1995 Prof. Hanukoglu was elected as the Chairman of the Professors for a Strong Israel, a self-described "non-partisan organization of academics united by a shared concern for the security and the Jewish character of the State of Israel." From 1996 to 1999 he served as the Science Adviser to the Prime Minister of Israel Benjamin Netanyahu. Hanukoglu was placed as an honorary candidate on the Herut – The National Movement list.[42]

In 2003 he was appointed as the scientific adviser to the Mayor of Rishon-Lezion for establishing the Jewish Nobel Prize Laureate Boulevard Outdoor Museum. Since 1996 he has served as a founding member of the Ariel Center for Policy Research executive board.[40]

References

  1. ↑ http://www.inn.co.il/Besheva/Article.aspx/1541
  2. ↑ http://www.science.co.il/About.php
  3. ↑ Hanukoglu I, Tanese N, Fuchs E (Feb 1983). "Complementary DNA sequence of a human cytoplasmic actin. Interspecies divergence of 3' non-coding regions". Journal of Molecular Biology. 163 (4): 673–8. doi:10.1016/0022-2836(83)90117-1. PMID 6842590.
  4. ↑ Hanukoglu I, Fuchs E (Nov 1982). "The cDNA sequence of a human epidermal keratin: divergence of sequence but conservation of structure among intermediate filament proteins.". Cell. 31 (1): 243–252. doi:10.1016/0092-8674(82)90424-X. PMID 6186381.
  5. ↑ Hanukoglu I, Fuchs E (Jul 1983). "The cDNA sequence of a Type II cytoskeletal keratin reveals constant and variable structural domains among keratins.". Cell. 33 (3): 915–924. doi:10.1016/0092-8674(83)90034-X. PMID 6191871.
  6. ↑ Lee CH, Kim MS, Chung BM, Leahy DJ, Coulombe PA (Jul 2012). "Structural basis for heteromeric assembly and perinuclear organization of keratin filaments". Nature Structural & Molecular Biology. 19 (7): 707–15. doi:10.1038/nsmb.2330. PMC 3864793Freely accessible. PMID 22705788.
  7. ↑ Hanukoglu I, Ezra L (Jan 2014). "Proteopedia: Coiled-coil structure of keratins.". Biochem Mol Biol Educ. 42 (1): 93–94. doi:10.1002/bmb.20746. PMID 24265184.
  8. 1 2 Hanukoglu I, Spitsberg V, Bumpus JA, Dus KM, Jefcoate CR (May 1981). "Adrenal mitochondrial cytochrome P-450scc. Cholesterol and adrenodoxin interactions at equilibrium and during turnover". The Journal of Biological Chemistry. 256 (9): 4321–8. PMID 7217084.
  9. ↑ Hanukoglu I (Dec 1992). "Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis". The Journal of Steroid Biochemistry and Molecular Biology. 43 (8): 779–804. doi:10.1016/0960-0760(92)90307-5. PMID 22217824.
  10. ↑ Hanukoglu I, Suh BS, Himmelhoch S, Amsterdam A (October 1990). "Induction and mitochondrial localization of cytochrome P450scc system enzymes in normal and transformed ovarian granulosa cells". The Journal of Cell Biology. 111 (4): 1373–81. doi:10.1083/jcb.111.4.1373. PMC 2116250Freely accessible. PMID 2170421.
  11. ↑ Hanukoglu I, Jefcoate CR (Apr 1980). "Mitochondrial cytochrome P-450scc. Mechanism of electron transport by adrenodoxin" (PDF). The Journal of Biological Chemistry. 255 (7): 3057–61. PMID 6766943.
  12. ↑ Hanukoglu I, Hanukoglu Z (May 1986). "Stoichiometry of mitochondrial cytochromes P-450, adrenodoxin and adrenodoxin reductase in adrenal cortex and corpus luteum. Implications for membrane organization and gene regulation". European Journal of Biochemistry. 157 (1): 27–31. doi:10.1111/j.1432-1033.1986.tb09633.x. PMID 3011431.
  13. ↑ Hanukoglu I, Gutfinger T, Haniu M, Shively JE (Dec 1987). "Isolation of a cDNA for adrenodoxin reductase (ferredoxin-NADP+ reductase). Implications for mitochondrial cytochrome P-450 systems.". European Journal of Biochemistry. 169 (3): 449–455. doi:10.1111/j.1432-1033.1987.tb13632.x. PMID 3691502.
  14. 1 2 Hanukoglu I, Gutfinger T (Mar 1989). "cDNA sequence of adrenodoxin reductase. Identification of NADP-binding sites in oxidoreductases". European Journal of Biochemistry / FEBS. 180 (2): 479–84. doi:10.1111/j.1432-1033.1989.tb14671.x. PMID 2924777.
  15. ↑ Solish SB, Picado-Leonard J, Morel Y, Kuhn RW, Mohandas TK, Hanukoglu I, Miller WL (Oct 1988). "Human adrenodoxin reductase: two mRNAs encoded by a single gene on chromosome 17cen----q25 are expressed in steroidogenic tissues". Proceedings of the National Academy of Sciences of the United States of America. 85 (19): 7104–7108. doi:10.1073/pnas.85.19.7104. PMC 282132Freely accessible. PMID 2845396.
  16. ↑ Scrutton NS, Berry A, Perham RN (Jan 1990). "Redesign of the coenzyme specificity of a dehydrogenase by protein engineering". Nature. 343 (6253): 38–43. doi:10.1038/343038a0. PMID 2296288.
  17. ↑ Ziegler GA, Vonrhein C, Hanukoglu I, Schulz GE (Jun 1999). "The structure of adrenodoxin reductase of mitochondrial P450 systems: electron transfer for steroid biosynthesis". Journal of Molecular Biology. 289 (4): 981–90. doi:10.1006/jmbi.1999.2807. PMID 10369776.
  18. ↑ Hanukoglu I, Rapoport R, Weiner L, Sklan D (September 1993). "Electron leakage from the mitochondrial NADPH-adrenodoxin reductase-adrenodoxin-P450scc (cholesterol side chain cleavage) system". Archives of Biochemistry and Biophysics. 305 (2): 489–98. doi:10.1006/abbi.1993.1452. PMID 8396893.
  19. ↑ Rapoport R, Sklan D, Hanukoglu I (10 March 1995). "Electron leakage from the adrenal cortex mitochondrial P450scc and P450c11 systems: NADPH and steroid dependence.". Archives of Biochemistry and Biophysics. 317 (2): 412–6. doi:10.1006/abbi.1995.1182. PMID 7893157.
  20. ↑ Hanukoglu I (2006). "Antioxidant protective mechanisms against reactive oxygen species (ROS) generated by mitochondrial P450 systems in steroidogenic cells". Drug Metabolism Reviews. 38 (1-2): 171–96. doi:10.1080/03602530600570040. PMID 16684656.
  21. ↑ Rapoport R, Sklan D, Wolfenson D, Shaham-Albalancy A, Hanukoglu I (March 1998). "Antioxidant capacity is correlated with steroidogenic status of the corpus luteum during the bovine estrous cycle". Biochim. Biophys. Acta. 1380 (1): 133–40. doi:10.1016/S0304-4165(97)00136-0. PMID 9545562.
  22. ↑ Hanukoglu I, Feuchtwanger R, Hanukoglu A (Nov 1990). "Mechanism of corticotropin and cAMP induction of mitochondrial cytochrome P450 system enzymes in adrenal cortex cells" (PDF). The Journal of Biological Chemistry. 265 (33): 20602–8. PMID 2173715.
  23. ↑ Raikhinstein M, Hanukoglu I (Nov 1993). "Mitochondrial-genome-encoded RNAs: differential regulation by corticotropin in bovine adrenocortical cells". Proceedings of the National Academy of Sciences of the United States of America. 90 (22): 10509–13. doi:10.1073/pnas.90.22.10509. PMC 47806Freely accessible. PMID 7504267.
  24. ↑ Hanukoglu A, Fried D, Nakash I, Hanukoglu I (Nov 1995). "Selective increases in adrenal steroidogenic capacity during acute respiratory disease in infants.". Eur J Endocrinol. 133 (5): 552–6. doi:10.1530/eje.0.1330552. PMID 7581984.
  25. ↑ Raikhinstein M, Zohar M, Hanukoglu I (Feb 1994). "cDNA cloning and sequence analysis of the bovine adrenocorticotropic hormone (ACTH) receptor". Biochimica et Biophysica Acta. 1220 (3): 329–32. doi:10.1016/0167-4889(94)90157-0. PMID 8305507.
  26. ↑ Hanukoglu, I. (Dec 1992). "Current research on steroid metabolism: transition from biochemistry to molecular-cell biology.". J Steroid Biochem Mol Biol. 43 (8): 745–9. doi:10.1016/0960-0760(92)90304-2. PMID 22217821.
  27. ↑ Hanukoglu A (November 1991). "Type I pseudohypoaldosteronism includes two clinically and genetically distinct entities with either renal or multiple target organ defects". The Journal of Clinical Endocrinology and Metabolism. 73 (5): 936–44. doi:10.1210/jcem-73-5-936. PMID 1939532.
  28. ↑ Strautnieks SS, Thompson RJ, Hanukoglu A, Dillon MJ, Hanukoglu I, Kuhnle U, Seckl J, Gardiner RM, Chung E (February 1996). "Localisation of pseudohypoaldosteronism genes to chromosome 16p12.2-13.11 and 12p13.1-pter by homozygosity mapping". Human Molecular Genetics. 5 (2): 293–9. doi:10.1093/hmg/5.2.293. PMID 8824886.
  29. ↑ Chang SS, Grunder S, Hanukoglu A, Rösler A, Mathew PM, Hanukoglu I, Schild L, Lu Y, Shimkets RA, Nelson-Williams C, Rossier BC, Lifton RP (March 1996). "Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1". Nature Genetics. 12 (3): 248–53. doi:10.1038/ng0396-248. PMID 8589714.
  30. ↑ Saxena A, Hanukoglu I, Saxena D, Thompson RJ, Gardiner RM, Hanukoglu A (July 2002). "Novel mutations responsible for autosomal recessive multisystem pseudohypoaldosteronism and sequence variants in epithelial sodium channel alpha-, beta-, and gamma-subunit genes". The Journal of Clinical Endocrinology and Metabolism. 87 (7): 3344–50. doi:10.1210/jcem.87.7.8674. PMID 12107247.
  31. ↑ Edelheit O, Hanukoglu I, Gizewska M, Kandemir N, Tenenbaum-Rakover Y, Yurdakök M, Zajaczek S, Hanukoglu A (May 2005). "Novel mutations in epithelial sodium channel (ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism". Clinical Endocrinology. 62 (5): 547–53. doi:10.1111/j.1365-2265.2005.02255.x. PMID 15853823.
  32. ↑ Hanukoglu I, Hanukoglu A (April 2016). "Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases". Gene. 579 (2): 95–132. doi:10.1016/j.gene.2015.12.061. PMC 4756657Freely accessible. PMID 26772908.
  33. ↑ Hanukoglu A, Edelheit O, Shriki Y, Gizewska M, Dascal N, Hanukoglu I (September 2008). "Renin-aldosterone response, urinary Na/K ratio and growth in pseudohypoaldosteronism patients with mutations in epithelial sodium channel (ENaC) subunit genes". The Journal of Steroid Biochemistry and Molecular Biology. 111 (3-5): 268–74. doi:10.1016/j.jsbmb.2008.06.013. PMID 18634878.
  34. ↑ Edelheit O, Hanukoglu I, Shriki Y, Tfilin M, Dascal N, Gillis D, Hanukoglu A (March 2010). "Truncated beta epithelial sodium channel (ENaC) subunits responsible for multi-system pseudohypoaldosteronism support partial activity of ENaC". The Journal of Steroid Biochemistry and Molecular Biology. 119 (1-2): 84–8. doi:10.1016/j.jsbmb.2010.01.002. PMID 20064610.
  35. ↑ Edelheit O, Hanukoglu I, Dascal N, Hanukoglu A (April 2011). "Identification of the roles of conserved charged residues in the extracellular domain of an epithelial sodium channel (ENaC) subunit by alanine mutagenesis". American Journal of Physiology. Renal Physiology. 300 (4): F887–97. doi:10.1152/ajprenal.00648.2010. PMID 21209000.
  36. ↑ Edelheit O, Ben-Shahar R, Dascal N, Hanukoglu A, Hanukoglu I (April 2014). "Conserved charged residues at the surface and interface of epithelial sodium channel subunits--roles in cell surface expression and the sodium self-inhibition response". The FEBS Journal. 281 (8): 2097–111. doi:10.1111/febs.12765. PMID 24571549.
  37. ↑ Hanukoglu I (August 2016). "ASIC and ENaC type sodium channels: Conformational states and the structures of the ion selectivity filters". The FEBS Journal. doi:10.1111/febs.13840. PMID 27580245.
  38. 1 2 Enuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A (March 2012). "Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways". Histochemistry and Cell Biology. 137 (3): 339–53. doi:10.1007/s00418-011-0904-1. PMID 22207244.
  39. ↑ Israel Hanukoglu. Brief Biography
  40. 1 2 Israel Hanukoglu. Curriculum Vitae
  41. ↑ Tsueng G, Good BM, Ping P, Golemis E, Hanukoglu I, van Wijnen AJ, Su AI (5 November 2016). "Gene Wiki Reviews-Raising the quality and accessibility of information about the human genome.". Gene. 592 (2): 235–8. doi:10.1016/j.gene.2016.04.053. PMID 27150585.
  42. ↑ Candidates for the 16th Knesset Israel Ministry of Foreign Affairs

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