Faculty Appointments
Research Professor of Biochemistry
Education
Ph.D., Bioorganic Chemistry, Institute of Bioorganic Chemistry, Minsk, BelarusM.S., Biochemistry, Belarusian State University, Minsk, Belarus
Office Address
622A RRB 2200 Pierce Ave
Nashville, TN 37232
Nashville, TN 37232
Publications
Hargrove TY, Lamb DC, Wawrzak Z, Hull M, Kelly SL, Guengerich FP, Lepesheva GI. Identification of Potent and Selective Inhibitors of Acanthamoeba: Structural Insights into Sterol 14a-Demethylase as a Key Drug Target. J Med Chem [print-electronic]. 2024 Apr 4/29/2024; PMID: 38683753, DOI: 10.1021/acs.jmedchem.4c00303, ISSN: 1520-4804.
McCarty KD, Tateishi Y, Hargrove TY, Lepesheva GI, Guengerich FP. Oxygen-18 Labeling Reveals a Mixed Fe-O Mechanism in the Last Step of Cytochrome P450 51 Sterol 14a-Demethylation. Angew Chem Int Ed Engl [print-electronic]. 2024 Jan 1/11/2024; e202317711. PMID: 38206808, DOI: 10.1002/anie.202317711, ISSN: 1521-3773.
McCarty KD, Sullivan ME, Tateishi Y, Hargrove TY, Lepesheva GI, Guengerich FP. Processive kinetics in the three-step lanosterol 14a-demethylation reaction catalyzed by human cytochrome P450 51A1. J Biol Chem [print-electronic]. 2023 May 5/18/2023; 104841. PMID: 37209823, PII: S0021-9258(23)01869-0, DOI: 10.1016/j.jbc.2023.104841, ISSN: 1083-351X.
Goldstone JV, Lamb DC, Kelly SL, Lepesheva GI, Stegeman JJ. Structural modeling of cytochrome P450 51 from a deep-sea fish points to a novel structural feature in other CYP51s. J Inorg Biochem [print-electronic]. 2023 Apr 4/28/2023; 245: 112241. PMID: 37209461, PII: S0162-0134(23)00123-X, DOI: 10.1016/j.jinorgbio.2023.112241, ISSN: 1873-3344.
Hargrove TY, Lamb DC, Smith JA, Wawrzak Z, Kelly SL, Lepesheva GI. Unravelling the role of transient redox partner complexes in P450 electron transfer mechanics. Sci Rep. 2022 Sep 9/28/2022; 12(1): 16232. PMID: 36171457, PMCID: PMC9519919, PII: 10.1038/s41598-022-20671-0, DOI: 10.1038/s41598-022-20671-0, ISSN: 2045-2322.
Hargrove TY, Wawrzak Z, Rachakonda G, Nes WD, Villalta F, Guengerich FP, Lepesheva GI. Relaxed Substrate Requirements of Sterol 14a-Demethylase from Naegleria fowleri Are Accompanied by Resistance to Inhibition. J Med Chem [print-electronic]. 2021 Nov 11/29/2021; PMID: 34842434, DOI: 10.1021/acs.jmedchem.1c01710, ISSN: 1520-4804.
Mercorelli B, Celegato M, Luganini A, Gribaudo G, Lepesheva G, Loregian A. The Antifungal Drug Isavuconazole Inhibits the Replication of Human Cytomegalovirus (HCMV) and Acts Synergistically with Anti-HCMV Drugs. Antiviral Res. c2021 Mar 3/12/2021; PMID: 33722615.
Lamb DC, Hargrove TY, Zhao B, Wawrzak Z, Goldstone JV, Nes WD, Kelly SL, Waterman MR, Stegeman JJ, Lepesheva GI. Concerning P450 evolution: Structural Analyses Support Bacterial Origin of Sterol 14a-Demethylases. Mol Biol Evol. 2021 Mar 3/9/2021; 38(3): 952-67. PMID: 33031537, PII: 5919591, DOI: 10.1093/molbev/msaa260, ISSN: 1537-1719.
Mercorelli B, Luganini A, Celegato M, Palù G, Gribaudo G, Lepesheva GI, Loregian A. The Clinically Approved Antifungal Drug Posaconazole Inhibits Human Cytomegalovirus Replication. Antimicrob. Agents Chemother [print-electronic]. 2020 Jul 7/20/2020; PMID: 32690644, PII: AAC.00056-20, DOI: 10.1128/AAC.00056-20, ISSN: 1098-6596.
Hargrove TY, Wawrzak Z, Guengerich FP, Lepesheva GI. A requirement for an active proton delivery network supports a Compound I mediated C-C bond cleavage in CYP51 catalysis. J. Biol. Chem [print-electronic]. 2020 Jun 6/3/2020; PMID: 32493730, PII: RA120.014064, DOI: 10.1074/jbc.RA120.014064, ISSN: 1083-351X.
Wang X, Cal M, Kaiser M, Buckner FS, Lepesheva GI, Sanford AG, Wallick AI, Davis PH, Vennerstrom JL. A new chemotype with promise against Trypanosoma cruzi. Bioorg. Med. Chem. Lett [print-electronic]. 2020 Jan 1/1/2020; 30(1): 126778. PMID: 31706668, PMCID: PMC6892603, PII: S0960-894X(19)30743-7, DOI: 10.1016/j.bmcl.2019.126778, ISSN: 1464-3405.
Friggeri L, Hargrove TY, Wawrzak Z, Guengerich FP, Lepesheva GI. Validation of Human Sterol 14a-Demethylase (CYP51) Druggability: Structure-Guided Design, Synthesis, and Evaluation of Stoichiometric, Functionally Irreversible Inhibitors. J. Med. Chem [print-electronic]. 2019 Nov 11/27/2019; 62(22): 10391-401. PMID: 31663733, PMCID: PMC6881533, DOI: 10.1021/acs.jmedchem.9b01485, ISSN: 1520-4804.
Guedes-da-Silva FH, Batista DDGJ, Da Silva CF, Pavão BP, Batista MM, Moreira OC, Souza LRQ, Britto C, Rachakonda G, Villalta F, Lepesheva GI, Soeiro MNC. Successful Aspects of the Coadministration of Sterol 14a-Demethylase Inhibitor VFV and Benznidazole in Experimental Mouse Models of Chagas Disease Caused by the Drug-Resistant Strain of Trypanosoma cruzi. ACS Infect Dis [print-electronic]. 2019 Mar 3/8/2019; 5(3): 365-71. PMID: 30625275, PMCID: PMC6408276, DOI: 10.1021/acsinfecdis.8b00253, ISSN: 2373-8227.
Friggeri L, Hargrove TY, Rachakonda G, Blobaum AL, Fisher P, de Oliveira GM, da Silva CF, Soeiro MNC, Nes WD, Lindsley CW, Villalta F, Guengerich FP, Lepesheva GI. Sterol 14a-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae. J. Med. Chem [print-electronic]. 2018 Nov 11/19/2018; PMID: 30451500, DOI: 10.1021/acs.jmedchem.8b01671, ISSN: 1520-4804.
Hargrove TY, Wawrzak Z, Fisher PM, Child SA, Nes WD, Guengerich FP, Waterman MR, Lepesheva GI. Binding of a physiological substrate causes large-scale conformational reorganization in cytochrome P450 51. J. Biol. Chem [print-electronic]. 2018 Oct 10/16/2018; PMID: 30327430, PII: RA118.005850, DOI: 10.1074/jbc.RA118.005850, ISSN: 1083-351X.
Friggeri L, Hargrove TY, Wawrzak Z, Blobaum AL, Rachakonda G, Lindsley CW, Villalta F, Nes WD, Botta M, Guengerich FP, Lepesheva GI. Sterol 14a-Demethylase Structure-Based Design of VNI (( R)- N-(1-(2,4-Dichlorophenyl)-2-(1 H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)) Derivatives To Target Fungal Infections: Synthesis, Biological Evaluation, and Crystallographic Analysis. J. Med. Chem [print-electronic]. 2018 Jun 6/25/2018; PMID: 29894182, DOI: 10.1021/acs.jmedchem.8b00641, ISSN: 1520-4804.
Lepesheva GI, Friggeri L, Waterman MR. CYP51 as drug targets for fungi and protozoan parasites: past, present and future. Parasitology [print-electronic]. 2018 Apr 4/12/2018; 1-17. PMID: 29642960, PII: S0031182018000562, DOI: 10.1017/S0031182018000562, ISSN: 1469-8161.
Lepesheva G, Christov P, Sulikowski GA, Kim K. A convergent, scalable and stereoselective synthesis of azole CYP51 inhibitors. Tetrahedron Lett [print-electronic]. 2017 Nov 11/8/2017; 58(45): 4248-50. PMID: 29371747, PMCID: PMC5777588, DOI: 10.1016/j.tetlet.2017.09.070, ISSN: 0040-4039.
Hargrove TY, Garvey EP, Hoekstra WJ, Yates CM, Wawrzak Z, Rachakonda G, Villalta F, Lepesheva GI. Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14a-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity. Antimicrob. Agents Chemother [electronic-print]. 2017 Jul; 61(7): PMID: 28461309, PMCID: PMC5487673, PII: AAC.00570-17, DOI: 10.1128/AAC.00570-17, ISSN: 1098-6596.
Mwenechanya R, Kovárová J, Dickens NJ, Mudaliar M, Herzyk P, Vincent IM, Weidt SK, Burgess KE, Burchmore RJS, Pountain AW, Smith TK, Creek DJ, Kim DH, Lepesheva GI, Barrett MP. Sterol 14a-demethylase mutation leads to amphotericin B resistance in Leishmania mexicana. PLoS Negl Trop Dis. 2017 Jun; 11(6): e0005649. PMID: 28622334, PMCID: PMC5498063, PII: PNTD-D-16-02188, DOI: 10.1371/journal.pntd.0005649, ISSN: 1935-2735.
Porta EOJ, Jäger SN, Nocito I, Lepesheva GI, Serra EC, Tekwani BL, Labadie GR. Antitrypanosomal and antileishmanial activity of prenyl-1,2,3-triazoles. Medchemcomm [print-electronic]. 2017 May 5/1/2017; 8(5): 1015-21. PMID: 28993794, PMCID: PMC5629980, DOI: 10.1039/C7MD00008A, ISSN: 2040-2503.
Hargrove TY, Friggeri L, Wawrzak Z, Qi A, Hoekstra WJ, Schotzinger RJ, York JD, Guengerich FP, Lepesheva GI. Structural Analyses of Candida albicans Sterol 14a-Demethylase Complexed with Azole Drugs Address the Molecular Basis of Azole-mediated Inhibition of Fungal Sterol Biosynthesis. J. Biol. Chem [print-electronic]. 2017 Mar 3/3/2017; PMID: 28258218, PII: M117.778308, DOI: 10.1074/jbc.M117.778308, ISSN: 1083-351X.
Guedes-da-Silva FH, Batista DG, Da Silva CF, De Araújo JS, Pavão BP, Simões-Silva MR, Meuser MB, Demarque KC, Moreira OC, Britto C, Lepesheva GI, Soeiro MN. Anti-trypanosomal activity of sterol 14a-demethylase (CYP51) inhibitors VNI and VFV in the Swiss mouse models of Chagas disease induced by the Y strain Trypanosoma cruzi. Antimicrob. Agents Chemother [print-electronic]. 2017 Feb 2/6/2017; PMID: 28167559, PII: AAC.02098-16, DOI: 10.1128/AAC.02098-16, ISSN: 1098-6596.
Hargrove TY, Friggeri L, Wawrzak Z, Sivakumaran S, Yazlovitskaya EM, Hiebert SW, Guengerich FP, Waterman MR, Lepesheva GI. Human sterol 14a-demethylase (CYP51) as a target for anticancer chemotherapy: Towards structure-aided drug design. J. Lipid Res [print-electronic]. 2016 Jun 6/16/2016; PMID: 27313059, PII: jlr.M069229, DOI: 10.1194/jlr.M069229, ISSN: 1539-7262.
Yu X, Nandekar P, Mustafa G, Cojocaru V, Lepesheva GI, Wade RC. Ligand tunnels in T. brucei and human CYP51: Insights for parasite-specific drug design. Biochim. Biophys. Acta [print-electronic]. 2016 Jan; 1860(1 Pt A): 67-78. PMID: 26493722, PMCID: PMC4689311, PII: S0304-4165(15)00287-1, DOI: 10.1016/j.bbagen.2015.10.015, ISSN: 0006-3002.
Hoekstra WJ, Hargrove TY, Wawrzak Z, Batista DD, da Silva CF, Nefertiti AS, Rachakonda G, Schotzinger RJ, Villalta F, Soeiro MN, Lepesheva GI. Antiparasitic effect in vitro, activity in a murine model of Chagas disease, and structural characterization in complex with the target enzyme CYP51 from Trypanosoma cruzi of the potent clinical candidate VT-1161. Antimicrob. Agents Chemother. 2015 Dec 12/7/2015; 60(2): 1058-66. PMID: 26643331, PII: AAC.02287-15, DOI: 10.1128/AAC.02287-15, ISSN: 1098-6596.
Guedes-da-Silva FH, Batista DG, da Silva CF, Meuser MB, Simões-Silva MR, de Araújo JS, Ferreira CG, Moreira OC, Britto C, Lepesheva GI, Soeiro Mde N. Different Therapeutic Outcomes of Benznidazole and VNI Treatments in Different Genders in Mouse Experimental Models of Trypanosoma cruzi Infection. Antimicrob. Agents Chemother [print-electronic]. 2015 Dec; 59(12): 7564-70. PMID: 26416857, PMCID: PMC4649169, PII: AAC.01294-15, DOI: 10.1128/AAC.01294-15, ISSN: 1098-6596.
Lepesheva GI, Hargrove TY, Rachakonda G, Wawrzak Z, Pomel S, Cojean S, Nde PN, Nes WD, Locuson CW, Calcutt MW, Waterman MR, Daniels JS, Loiseau PM, Villalta F. VFV as a New Effective CYP51 Structure-Derived Drug Candidate for Chagas Disease and Visceral Leishmaniasis. J. Infect. Dis [print-electronic]. 2015 Nov 11/1/2015; 212(9): 1439-48. PMID: 25883390, PMCID: PMC4601915, PII: jiv228, DOI: 10.1093/infdis/jiv228, ISSN: 1537-6613.
Hargrove TY, Wawrzak Z, Lamb DC, Guengerich FP, Lepesheva GI. Structure-Functional Characterization of Cytochrome P450 Sterol 14a-Demethylase (CYP51B) from Aspergillus fumigatus and Molecular Basis for the Development of Antifungal Drugs. J. Biol. Chem [print-electronic]. 2015 Sep 9/25/2015; 290(39): 23916-34. PMID: 26269599, PMCID: PMC4583043, PII: M115.677310, DOI: 10.1074/jbc.M115.677310, ISSN: 1083-351X.
Papadopoulou MV, Bloomer WD, Lepesheva GI, Rosenzweig HS, Kaiser M, Aguilera-Venegas B, Wilkinson SR, Chatelain E, Ioset JR. Novel 3-nitrotriazole-based amides and carbinols as bifunctional antichagasic agents. J. Med. Chem [print-electronic]. 2015 Feb 2/12/2015; 58(3): 1307-19. PMID: 25580906, PMCID: PMC4337820, DOI: 10.1021/jm5015742, ISSN: 1520-4804.
Yu X, Cojocaru V, Mustafa G, Salo-Ahen OM, Lepesheva GI, Wade RC. Dynamics of CYP51: implications for function and inhibitor design. J. Mol. Recognit [print-electronic]. 2015 Feb; 28(2): 59-73. PMID: 25601796, PMCID: PMC4337246, DOI: 10.1002/jmr.2412, ISSN: 1099-1352.
Cherkesova TS, Hargrove TY, Vanrell MC, Ges I, Usanov SA, Romano PS, Lepesheva GI. Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition. FEBS Lett [print-electronic]. 2014 Nov 11/3/2014; 588(21): 3878-85. PMID: 25217832, PMCID: PMC4252588, PII: S0014-5793(14)00657-7, DOI: 10.1016/j.febslet.2014.08.030, ISSN: 1873-3468.
Friggeri L, Hargrove TY, Rachakonda G, Williams AD, Wawrzak Z, Di Santo R, De Vita D, Waterman MR, Tortorella S, Villalta F, Lepesheva GI. Structural basis for rational design of inhibitors targeting Trypanosoma cruzi sterol 14a-demethylase: two regions of the enzyme molecule potentiate its inhibition. J. Med. Chem [print-electronic]. 2014 Aug 8/14/2014; 57(15): 6704-17. PMID: 25033013, PMCID: PMC4136671, DOI: 10.1021/jm500739f, ISSN: 1520-4804.
Lepesheva GI. Design or screening of drugs for the treatment of Chagas disease: what shows the most promise?. Expert Opin Drug Discov [print-electronic]. 2013 Dec; 8(12): 1479-89. PMID: 24079515, PMCID: PMC3867292, DOI: 10.1517/17460441.2013.845554, ISSN: 1746-045X.
Suryadevara PK, Racherla KK, Olepu S, Norcross NR, Tatipaka HB, Arif JA, Planer JD, Lepesheva GI, Verlinde CL, Buckner FS, Gelb MH. Dialkylimidazole inhibitors of Trypanosoma cruzi sterol 14a-demethylase as anti-Chagas disease agents. Bioorg. Med. Chem. Lett [print-electronic]. 2013 Dec 12/1/2013; 23(23): 6492-9. PMID: 24120539, PMCID: PMC4111244, PII: S0960-894X(13)00944-X, DOI: 10.1016/j.bmcl.2013.08.015, ISSN: 1464-3405.
Hargrove TY, Wawrzak Z, Alexander PW, Chaplin JH, Keenan M, Charman SA, Perez CJ, Waterman MR, Chatelain E, Lepesheva GI. Complexes of Trypanosoma cruzi sterol 14a-demethylase (CYP51) with two pyridine-based drug candidates for Chagas disease: structural basis for pathogen selectivity. J. Biol. Chem [print-electronic]. 2013 Nov 11/1/2013; 288(44): 31602-15. PMID: 24047900, PMCID: PMC3814756, PII: M113.497990, DOI: 10.1074/jbc.M113.497990, ISSN: 1083-351X.
Soeiro Mde N, de Souza EM, da Silva CF, Batista Dda G, Batista MM, Pavão BP, Araújo JS, Aiub CA, da Silva PB, Lionel J, Britto C, Kim K, Sulikowski G, Hargrove TY, Waterman MR, Lepesheva GI. In vitro and in vivo studies of the antiparasitic activity of sterol 14a-demethylase (CYP51) inhibitor VNI against drug-resistant strains of Trypanosoma cruzi. Antimicrob. Agents Chemother [print-electronic]. 2013 Sep; 57(9): 4151-63. PMID: 23774435, PMCID: PMC3754355, PII: AAC.00070-13, DOI: 10.1128/AAC.00070-13, ISSN: 1098-6596.
Villalta F, Dobish MC, Nde PN, Kleshchenko YY, Hargrove TY, Johnson CA, Waterman MR, Johnston JN, Lepesheva GI. VNI cures acute and chronic experimental Chagas disease. J. Infect. Dis [print-electronic]. 2013 Aug 8/1/2013; 208(3): 504-11. PMID: 23372180, PMCID: PMC3698996, PII: jit042, DOI: 10.1093/infdis/jit042, ISSN: 1537-6613.
Andriani G, Amata E, Beatty J, Clements Z, Coffey BJ, Courtemanche G, Devine W, Erath J, Juda CE, Wawrzak Z, Wood JT, Lepesheva GI, Rodriguez A, Pollastri MP. Antitrypanosomal lead discovery: identification of a ligand-efficient inhibitor of Trypanosoma cruzi CYP51 and parasite growth. J. Med. Chem [print-electronic]. 2013 Mar 3/28/2013; 56(6): 2556-67. PMID: 23448316, PMCID: PMC3612894, DOI: 10.1021/jm400012e, ISSN: 1520-4804.
Dobish MC, Villalta F, Waterman MR, Lepesheva GI, Johnston JN. Organocatalytic, enantioselective synthesis of VNI: a robust therapeutic development platform for Chagas, a neglected tropical disease. Org. Lett [print-electronic]. 2012 Dec 12/21/2012; 14(24): 6322-5. PMID: 23214987, PMCID: PMC3528807, DOI: 10.1021/ol303092v, ISSN: 1523-7052.
Hargrove TY, Kim K, de Nazaré Correia Soeiro M, da Silva CF, Batista DD, Batista MM, Yazlovitskaya EM, Waterman MR, Sulikowski GA, Lepesheva GI. CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds. Int J Parasitol Drugs Drug Resist [print-electronic]. 2012 Dec; 2: 178-86. PMID: 23504044, PMCID: PMC3596085, ISSN: 2211-3207.
Buckner FS, Bahia MT, Suryadevara PK, White KL, Shackleford DM, Chennamaneni NK, Hulverson MA, Laydbak JU, Chatelain E, Scandale I, Verlinde CL, Charman SA, Lepesheva GI, Gelb MH. Pharmacological characterization, structural studies, and in vivo activities of anti-Chagas disease lead compounds derived from tipifarnib. Antimicrob. Agents Chemother [print-electronic]. 2012 Sep; 56(9): 4914-21. PMID: 22777048, PMCID: PMC3421879, PII: AAC.06244-11, DOI: 10.1128/AAC.06244-11, ISSN: 1098-6596.
Nes CR, Singha UK, Liu J, Ganapathy K, Villalta F, Waterman MR, Lepesheva GI, Chaudhuri M, Nes WD. Novel sterol metabolic network of Trypanosoma brucei procyclic and bloodstream forms. Biochem. J. 2012 Apr 4/1/2012; 443(1): 267-77. PMID: 22176028, PMCID: PMC3491665, PII: BJ20111849, DOI: 10.1042/BJ20111849, ISSN: 1470-8728.
Hargrove TY, Wawrzak Z, Liu J, Waterman MR, Nes WD, Lepesheva GI. Structural complex of sterol 14a-demethylase (CYP51) with 14a-methylenecyclopropyl-Delta7-24, 25-dihydrolanosterol. J. Lipid Res [print-electronic]. 2012 Feb; 53(2): 311-20. PMID: 22135275, PMCID: PMC3269163, PII: jlr.M021865, DOI: 10.1194/jlr.M021865, ISSN: 0022-2275.
Hargrove TY, Wawrzak Z, Liu J, Nes WD, Waterman MR, Lepesheva GI. Substrate preferences and catalytic parameters determined by structural characteristics of sterol 14alpha-demethylase (CYP51) from Leishmania infantum. J. Biol. Chem [print-electronic]. 2011 Jul 7/29/2011; 286(30): 26838-48. PMID: 21632531, PMCID: PMC3143644, PII: M111.237099, DOI: 10.1074/jbc.M111.237099, ISSN: 1083-351X.
Lepesheva GI, Villalta F, Waterman MR. Targeting Trypanosoma cruzi sterol 14a-demethylase (CYP51). Adv. Parasitol. 2011; 75: 65-87. PMID: 21820552, PMCID: PMC3488290, PII: B978-0-12-385863-4.00004-6, DOI: 10.1016/B978-0-12-385863-4.00004-6, ISSN: 0065-308X.
Lepesheva GI, Waterman MR. Sterol 14alpha-demethylase (CYP51) as a therapeutic target for human trypanosomiasis and leishmaniasis. Curr Top Med Chem. 2011; 11(16): 2060-71. PMID: 21619513, PMCID: PMC3391166, PII: BSP/CTMC/E-Pub/-000127-11-16a, ISSN: 1873-4294.
Lepesheva GI, Waterman MR. Structural basis for conservation in the CYP51 family. Biochim. Biophys. Acta [print-electronic]. 2011 Jan; 1814(1): 88-93. PMID: 20547249, PMCID: PMC2962772, PII: S1570-9639(10)00164-0, DOI: 10.1016/j.bbapap.2010.06.006, ISSN: 0006-3002.
Lepesheva GI, Hargrove TY, Anderson S, Kleshchenko Y, Furtak V, Wawrzak Z, Villalta F, Waterman MR. Structural insights into inhibition of sterol 14alpha-demethylase in the human pathogen Trypanosoma cruzi. J. Biol. Chem [print-electronic]. 2010 Aug 8/13/2010; 285(33): 25582-90. PMID: 20530488, PMCID: PMC2919122, PII: M110.133215, DOI: 10.1074/jbc.M110.133215, ISSN: 1083-351X.
Lepesheva GI, Park HW, Hargrove TY, Vanhollebeke B, Wawrzak Z, Harp JM, Sundaramoorthy M, Nes WD, Pays E, Chaudhuri M, Villalta F, Waterman MR. Crystal structures of Trypanosoma brucei sterol 14alpha-demethylase and implications for selective treatment of human infections. J. Biol. Chem [print-electronic]. 2010 Jan 1/15/2010; 285(3): 1773-80. PMID: 19923211, PMCID: PMC2804335, PII: M109.067470, DOI: 10.1074/jbc.M109.067470, ISSN: 1083-351X.
Lamb DC, Lei L, Warrilow AG, Lepesheva GI, Mullins JG, Waterman MR, Kelly SL. The first virally encoded cytochrome p450. J. Virol [print-electronic]. 2009 Aug; 83(16): 8266-9. PMID: 19515774, PMCID: PMC2715754, PII: JVI.00289-09, DOI: 10.1128/JVI.00289-09, ISSN: 1098-5514.
Konkle ME, Hargrove TY, Kleshchenko YY, von Kries JP, Ridenour W, Uddin MJ, Caprioli RM, Marnett LJ, Nes WD, Villalta F, Waterman MR, Lepesheva GI. Indomethacin amides as a novel molecular scaffold for targeting Trypanosoma cruzi sterol 14alpha-demethylase. J. Med. Chem. 2009 May 5/14/2009; 52(9): 2846-53. PMID: 19354253, PMCID: PMC2744100, DOI: 10.1021/jm801643b, ISSN: 1520-4804.
Kraus JM, Verlinde CL, Karimi M, Lepesheva GI, Gelb MH, Buckner FS. Rational modification of a candidate cancer drug for use against Chagas disease. J. Med. Chem. 2009 Mar 3/26/2009; 52(6): 1639-47. PMID: 19239254, PMCID: PMC2715367, DOI: 10.1021/jm801313t, ISSN: 1520-4804.
Lepesheva GI, Hargrove TY, Kleshchenko Y, Nes WD, Villalta F, Waterman MR. CYP51: A major drug target in the cytochrome P450 superfamily. Lipids [print-electronic]. 2008 Dec; 43(12): 1117-25. PMID: 18769951, PMCID: PMC2715142, DOI: 10.1007/s11745-008-3225-y, ISSN: 0024-4201.
Lepesheva GI, Ott RD, Hargrove TY, Kleshchenko YY, Schuster I, Nes WD, Hill GC, Villalta F, Waterman MR. Sterol 14alpha-demethylase as a potential target for antitrypanosomal therapy: enzyme inhibition and parasite cell growth. Chem. Biol. 2007 Nov; 14(11): 1283-93. PMID: 18022567, PMCID: PMC2324070, PII: S1074-5521(07)00362-6, DOI: 10.1016/j.chembiol.2007.10.011, ISSN: 1074-5521.
Lepesheva GI, Seliskar M, Knutson CG, Stourman NV, Rozman D, Waterman MR. Conformational dynamics in the F/G segment of CYP51 from Mycobacterium tuberculosis monitored by FRET. Arch. Biochem. Biophys [print-electronic]. 2007 Aug 8/15/2007; 464(2): 221-7. PMID: 17585868, PMCID: PMC3042880, PII: S0003-9861(07)00271-8, DOI: 10.1016/j.abb.2007.05.017, ISSN: 0003-9861.
Lepesheva GI, Waterman MR. Sterol 14alpha-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms. Biochim. Biophys. Acta [print-electronic]. 2007 Mar; 1770(3): 467-77. PMID: 16963187, PMCID: PMC2324071, PII: S0304-4165(06)00214-5, DOI: 10.1016/j.bbagen.2006.07.018, ISSN: 0006-3002.
Lepesheva GI, Hargrove TY, Ott RD, Nes WD, Waterman MR. Biodiversity of CYP51 in trypanosomes. Biochem. Soc. Trans. 2006 Dec; 34(Pt 6): 1161-4. PMID: 17073776, PII: BST0341161, DOI: 10.1042/BST0341161, ISSN: 0300-5127.
Strushkevich NV, Harnastai IN, Lepesheva GI, Usanov SA. Role of C-terminal sequence of cytochrome P450scc in folding and functional activity. Biochemistry Mosc. 2006 Sep; 71(9): 1027-34. PMID: 17009958, PII: BCM71091269, ISSN: 0006-2979.
Zhou W, Lepesheva GI, Waterman MR, Nes WD. Mechanistic analysis of a multiple product sterol methyltransferase implicated in ergosterol biosynthesis in Trypanosoma brucei. J. Biol. Chem [print-electronic]. 2006 Mar 3/10/2006; 281(10): 6290-6. PMID: 16414960, PII: M511749200, DOI: 10.1074/jbc.M511749200, ISSN: 0021-9258.
Lepesheva GI, Zaitseva NG, Nes WD, Zhou W, Arase M, Liu J, Hill GC, Waterman MR. CYP51 from Trypanosoma cruzi: a phyla-specific residue in the B' helix defines substrate preferences of sterol 14alpha-demethylase. J. Biol. Chem [print-electronic]. 2006 Feb 2/10/2006; 281(6): 3577-85. PMID: 16321980, PII: M510317200, DOI: 10.1074/jbc.M510317200, ISSN: 0021-9258.
Lamb DC, Kim Y, Yermalitskaya LV, Yermalitsky VN, Lepesheva GI, Kelly SL, Waterman MR, Podust LM. A second FMN binding site in yeast NADPH-cytochrome P450 reductase suggests a mechanism of electron transfer by diflavin reductases. Structure. 2006 Jan; 14(1): 51-61. PMID: 16407065, PII: S0969-2126(05)00395-3, DOI: 10.1016/j.str.2005.09.015, ISSN: 0969-2126.
Waterman MR, Lepesheva GI. Sterol 14 alpha-demethylase, an abundant and essential mixed-function oxidase. Biochem. Biophys. Res. Commun [print-electronic]. 2005 Dec 12/9/2005; 338(1): 418-22. PMID: 16153595, PII: S0006-291X(05)01851-6, DOI: 10.1016/j.bbrc.2005.08.118, ISSN: 0006-291X.
Strushkevich NV, Azeva TN, Lepesheva GI, Usanov SA. Role of positively charged residues lys267, lys270, and arg411 of cytochrome p450scc (CYP11A1) in interaction with adrenodoxin. Biochemistry Mosc. 2005 Jun; 70(6): 664-71. PMID: 16038609, PII: BCM70060805, ISSN: 0006-2979.
Podust LM, Yermalitskaya LV, Lepesheva GI, Podust VN, Dalmasso EA, Waterman MR. Estriol bound and ligand-free structures of sterol 14alpha-demethylase. Structure. 2004 Nov; 12(11): 1937-45. PMID: 15530358, PII: S0969212604003363, DOI: 10.1016/j.str.2004.08.009, ISSN: 0969-2126.
Bellamine A, Lepesheva GI, Waterman MR. Fluconazole binding and sterol demethylation in three CYP51 isoforms indicate differences in active site topology. J. Lipid Res [print-electronic]. 2004 Nov; 45(11): 2000-7. PMID: 15314102, PII: M400239-JLR200, DOI: 10.1194/jlr.M400239-JLR200, ISSN: 0022-2275.
Lepesheva GI, Nes WD, Zhou W, Hill GC, Waterman MR. CYP51 from Trypanosoma brucei is obtusifoliol-specific. Biochemistry. 2004 Aug 8/24/2004; 43(33): 10789-99. PMID: 15311940, DOI: 10.1021/bi048967t, ISSN: 0006-2960.
Lepesheva GI, Waterman MR. CYP51--the omnipotent P450. Mol. Cell. Endocrinol. 2004 Feb 2/27/2004; 215(1-2): 165-70. PMID: 15026190, PII: S0303720703005148, DOI: 10.1016/j.mce.2003.11.016, ISSN: 0303-7207.
Lepesheva GI, Virus C, Waterman MR. Conservation in the CYP51 family. Role of the B' helix/BC loop and helices F and G in enzymatic function. Biochemistry. 2003 Aug 8/5/2003; 42(30): 9091-101. PMID: 12885242, DOI: 10.1021/bi034663f, ISSN: 0006-2960.
Usanov SA, Graham SE, Lepesheva GI, Azeva TN, Strushkevich NV, Gilep AA, Estabrook RW, Peterson JA. Probing the interaction of bovine cytochrome P450scc (CYP11A1) with adrenodoxin: evaluating site-directed mutations by molecular modeling. Biochemistry. 2002 Jul 7/2/2002; 41(26): 8310-20. PMID: 12081479, PII: bi0255928, ISSN: 0006-2960.
Lepesheva GI, Podust LM, Bellamine A, Waterman MR. Folding requirements are different between sterol 14alpha-demethylase (CYP51) from Mycobacterium tuberculosis and human or fungal orthologs. J. Biol. Chem [print-electronic]. 2001 Jul 7/27/2001; 276(30): 28413-20. PMID: 11373285, PII: M102767200, DOI: 10.1074/jbc.M102767200, ISSN: 0021-9258.
Azeva TN, Gilep AA, Lepesheva GI, Strushkevich NV, Usanov SA. Site-directed mutagenesis of cytochrome P450scc. II. Effect of replacement of the Arg425 and Arg426 residues on the structural and functional properties of the cytochrome P450scc. Biochemistry Mosc. 2001 May; 66(5): 564-75. PMID: 11405894, PII: BCM66050698, ISSN: 0006-2979.
Lepesheva GI, Azeva TN, Strushkevich NV, Gilep AA, Usanov SA. Site-directed mutagenesis of cytochrome P450scc (CYP11A1). Effect of lysine residue substitution on its structural and functional properties. Biochemistry Mosc. 2000 Dec; 65(12): 1409-18. PMID: 11173513, PII: BCM65121673, ISSN: 0006-2979.
Lepesheva GI, Strushkevich NV, Usanov SA. Conformational dynamics and molecular interaction reactions of recombinant cytochrome p450scc (CYP11A1) detected by fluorescence energy transfer. Biochim. Biophys. Acta. 1999 Sep 9/14/1999; 1434(1): 31-43. PMID: 10556557, PII: S0167-4838(99)00156-9, ISSN: 0006-3002.
Lepesheva GI, Azeva TN, Strushkevich NV, Adamovich TB, Cherkesova TS, Usanov SA. Comparative structural-functional characterization of recombinant and natural adrenodoxin. Interaction with cytochrome P450scc. Biochemistry Mosc. 1999 Sep; 64(9): 1079-88. PMID: 10521726, PII: BCM64091280, ISSN: 0006-2979.
Lepesheva GI, Usanov SA. Comparative structural and immunochemical characterization of recombinant and natural cytochrome p450scc (CYPXIAI). Biochemistry Mosc. 1998 Feb; 63(2): 224-34. PMID: 9526119, ISSN: 0006-2979.
Lepesheva GI, Usanov SA. Dynamics and functional activity of cytochrome P450scc selectively labeled with fluorescein isothiocyanate. Biochemistry Mosc. 1997 Jun; 62(6): 648-56. PMID: 9324423, ISSN: 0006-2979.
Lepesheva GI, Usanov SA. [The use of selective chemical modification of cytochrome P450scc (CYPXIA1) with fluorescein isothiocyanate for evaluation of intramolecular distances and conformational changes by fluorescent resonance energy transfer]. Biokhimiia. 1996 Aug; 61(8): 1395-407. PMID: 8962914, ISSN: 0320-9725.
Lepesheva GI, Turko IV, Ges' IA, Chashchin VL. [Direct detection of an antigen in immunoglobulin G Langmuir-Blodgett films based on a surface plasma resonance method and in a piezoelectric system]. Biokhimiia. 1994 Jul; 59(7): 939-45. PMID: 7948419, ISSN: 0320-9725.
Lepesheva GI, Turko IV, Shestakov VL, Chashchin VL. [IgG, modified with coproporphyrin I and the possibility of direct measurement of the antigen-antibody complex]. Biokhimiia. 1993 Jun; 58(6): 938-43. PMID: 8364116, ISSN: 0320-9725.
Lepesheva GI, Martsev SP. [Modification of a disulfide in the hinge region of rabbit IgG and study of the interaction of polyvalent ferritin antigen, protein A, and anti-IgG]. Biokhimiia. 1992 Jul; 57(7): 1089-99. PMID: 1391214, ISSN: 0320-9725.
Lepesheva GI, Martsev SP. [The use of biotin-streptavidin systems for enhancing the parameters of immunometric analysis]. Zh. Mikrobiol. Epidemiol. Immunobiol. 1990 Oct; (10): 121-5. PMID: 2075757, ISSN: 0372-9311.
A Requirement for an Active Proton Delivery Network Supports a Compound I Mediated C-C Bond Cleavage in CYP51 Catalysis. J. Biol.Chem.
McCarty KD, Tateishi Y, Hargrove TY, Lepesheva GI, Guengerich FP. Oxygen-18 Labeling Reveals a Mixed Fe-O Mechanism in the Last Step of Cytochrome P450 51 Sterol 14a-Demethylation. Angew Chem Int Ed Engl [print-electronic]. 2024 Jan 1/11/2024; e202317711. PMID: 38206808, DOI: 10.1002/anie.202317711, ISSN: 1521-3773.
McCarty KD, Sullivan ME, Tateishi Y, Hargrove TY, Lepesheva GI, Guengerich FP. Processive kinetics in the three-step lanosterol 14a-demethylation reaction catalyzed by human cytochrome P450 51A1. J Biol Chem [print-electronic]. 2023 May 5/18/2023; 104841. PMID: 37209823, PII: S0021-9258(23)01869-0, DOI: 10.1016/j.jbc.2023.104841, ISSN: 1083-351X.
Goldstone JV, Lamb DC, Kelly SL, Lepesheva GI, Stegeman JJ. Structural modeling of cytochrome P450 51 from a deep-sea fish points to a novel structural feature in other CYP51s. J Inorg Biochem [print-electronic]. 2023 Apr 4/28/2023; 245: 112241. PMID: 37209461, PII: S0162-0134(23)00123-X, DOI: 10.1016/j.jinorgbio.2023.112241, ISSN: 1873-3344.
Hargrove TY, Lamb DC, Smith JA, Wawrzak Z, Kelly SL, Lepesheva GI. Unravelling the role of transient redox partner complexes in P450 electron transfer mechanics. Sci Rep. 2022 Sep 9/28/2022; 12(1): 16232. PMID: 36171457, PMCID: PMC9519919, PII: 10.1038/s41598-022-20671-0, DOI: 10.1038/s41598-022-20671-0, ISSN: 2045-2322.
Hargrove TY, Wawrzak Z, Rachakonda G, Nes WD, Villalta F, Guengerich FP, Lepesheva GI. Relaxed Substrate Requirements of Sterol 14a-Demethylase from Naegleria fowleri Are Accompanied by Resistance to Inhibition. J Med Chem [print-electronic]. 2021 Nov 11/29/2021; PMID: 34842434, DOI: 10.1021/acs.jmedchem.1c01710, ISSN: 1520-4804.
Mercorelli B, Celegato M, Luganini A, Gribaudo G, Lepesheva G, Loregian A. The Antifungal Drug Isavuconazole Inhibits the Replication of Human Cytomegalovirus (HCMV) and Acts Synergistically with Anti-HCMV Drugs. Antiviral Res. c2021 Mar 3/12/2021; PMID: 33722615.
Lamb DC, Hargrove TY, Zhao B, Wawrzak Z, Goldstone JV, Nes WD, Kelly SL, Waterman MR, Stegeman JJ, Lepesheva GI. Concerning P450 evolution: Structural Analyses Support Bacterial Origin of Sterol 14a-Demethylases. Mol Biol Evol. 2021 Mar 3/9/2021; 38(3): 952-67. PMID: 33031537, PII: 5919591, DOI: 10.1093/molbev/msaa260, ISSN: 1537-1719.
Mercorelli B, Luganini A, Celegato M, Palù G, Gribaudo G, Lepesheva GI, Loregian A. The Clinically Approved Antifungal Drug Posaconazole Inhibits Human Cytomegalovirus Replication. Antimicrob. Agents Chemother [print-electronic]. 2020 Jul 7/20/2020; PMID: 32690644, PII: AAC.00056-20, DOI: 10.1128/AAC.00056-20, ISSN: 1098-6596.
Hargrove TY, Wawrzak Z, Guengerich FP, Lepesheva GI. A requirement for an active proton delivery network supports a Compound I mediated C-C bond cleavage in CYP51 catalysis. J. Biol. Chem [print-electronic]. 2020 Jun 6/3/2020; PMID: 32493730, PII: RA120.014064, DOI: 10.1074/jbc.RA120.014064, ISSN: 1083-351X.
Wang X, Cal M, Kaiser M, Buckner FS, Lepesheva GI, Sanford AG, Wallick AI, Davis PH, Vennerstrom JL. A new chemotype with promise against Trypanosoma cruzi. Bioorg. Med. Chem. Lett [print-electronic]. 2020 Jan 1/1/2020; 30(1): 126778. PMID: 31706668, PMCID: PMC6892603, PII: S0960-894X(19)30743-7, DOI: 10.1016/j.bmcl.2019.126778, ISSN: 1464-3405.
Friggeri L, Hargrove TY, Wawrzak Z, Guengerich FP, Lepesheva GI. Validation of Human Sterol 14a-Demethylase (CYP51) Druggability: Structure-Guided Design, Synthesis, and Evaluation of Stoichiometric, Functionally Irreversible Inhibitors. J. Med. Chem [print-electronic]. 2019 Nov 11/27/2019; 62(22): 10391-401. PMID: 31663733, PMCID: PMC6881533, DOI: 10.1021/acs.jmedchem.9b01485, ISSN: 1520-4804.
Guedes-da-Silva FH, Batista DDGJ, Da Silva CF, Pavão BP, Batista MM, Moreira OC, Souza LRQ, Britto C, Rachakonda G, Villalta F, Lepesheva GI, Soeiro MNC. Successful Aspects of the Coadministration of Sterol 14a-Demethylase Inhibitor VFV and Benznidazole in Experimental Mouse Models of Chagas Disease Caused by the Drug-Resistant Strain of Trypanosoma cruzi. ACS Infect Dis [print-electronic]. 2019 Mar 3/8/2019; 5(3): 365-71. PMID: 30625275, PMCID: PMC6408276, DOI: 10.1021/acsinfecdis.8b00253, ISSN: 2373-8227.
Friggeri L, Hargrove TY, Rachakonda G, Blobaum AL, Fisher P, de Oliveira GM, da Silva CF, Soeiro MNC, Nes WD, Lindsley CW, Villalta F, Guengerich FP, Lepesheva GI. Sterol 14a-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae. J. Med. Chem [print-electronic]. 2018 Nov 11/19/2018; PMID: 30451500, DOI: 10.1021/acs.jmedchem.8b01671, ISSN: 1520-4804.
Hargrove TY, Wawrzak Z, Fisher PM, Child SA, Nes WD, Guengerich FP, Waterman MR, Lepesheva GI. Binding of a physiological substrate causes large-scale conformational reorganization in cytochrome P450 51. J. Biol. Chem [print-electronic]. 2018 Oct 10/16/2018; PMID: 30327430, PII: RA118.005850, DOI: 10.1074/jbc.RA118.005850, ISSN: 1083-351X.
Friggeri L, Hargrove TY, Wawrzak Z, Blobaum AL, Rachakonda G, Lindsley CW, Villalta F, Nes WD, Botta M, Guengerich FP, Lepesheva GI. Sterol 14a-Demethylase Structure-Based Design of VNI (( R)- N-(1-(2,4-Dichlorophenyl)-2-(1 H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)) Derivatives To Target Fungal Infections: Synthesis, Biological Evaluation, and Crystallographic Analysis. J. Med. Chem [print-electronic]. 2018 Jun 6/25/2018; PMID: 29894182, DOI: 10.1021/acs.jmedchem.8b00641, ISSN: 1520-4804.
Lepesheva GI, Friggeri L, Waterman MR. CYP51 as drug targets for fungi and protozoan parasites: past, present and future. Parasitology [print-electronic]. 2018 Apr 4/12/2018; 1-17. PMID: 29642960, PII: S0031182018000562, DOI: 10.1017/S0031182018000562, ISSN: 1469-8161.
Lepesheva G, Christov P, Sulikowski GA, Kim K. A convergent, scalable and stereoselective synthesis of azole CYP51 inhibitors. Tetrahedron Lett [print-electronic]. 2017 Nov 11/8/2017; 58(45): 4248-50. PMID: 29371747, PMCID: PMC5777588, DOI: 10.1016/j.tetlet.2017.09.070, ISSN: 0040-4039.
Hargrove TY, Garvey EP, Hoekstra WJ, Yates CM, Wawrzak Z, Rachakonda G, Villalta F, Lepesheva GI. Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14a-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity. Antimicrob. Agents Chemother [electronic-print]. 2017 Jul; 61(7): PMID: 28461309, PMCID: PMC5487673, PII: AAC.00570-17, DOI: 10.1128/AAC.00570-17, ISSN: 1098-6596.
Mwenechanya R, Kovárová J, Dickens NJ, Mudaliar M, Herzyk P, Vincent IM, Weidt SK, Burgess KE, Burchmore RJS, Pountain AW, Smith TK, Creek DJ, Kim DH, Lepesheva GI, Barrett MP. Sterol 14a-demethylase mutation leads to amphotericin B resistance in Leishmania mexicana. PLoS Negl Trop Dis. 2017 Jun; 11(6): e0005649. PMID: 28622334, PMCID: PMC5498063, PII: PNTD-D-16-02188, DOI: 10.1371/journal.pntd.0005649, ISSN: 1935-2735.
Porta EOJ, Jäger SN, Nocito I, Lepesheva GI, Serra EC, Tekwani BL, Labadie GR. Antitrypanosomal and antileishmanial activity of prenyl-1,2,3-triazoles. Medchemcomm [print-electronic]. 2017 May 5/1/2017; 8(5): 1015-21. PMID: 28993794, PMCID: PMC5629980, DOI: 10.1039/C7MD00008A, ISSN: 2040-2503.
Hargrove TY, Friggeri L, Wawrzak Z, Qi A, Hoekstra WJ, Schotzinger RJ, York JD, Guengerich FP, Lepesheva GI. Structural Analyses of Candida albicans Sterol 14a-Demethylase Complexed with Azole Drugs Address the Molecular Basis of Azole-mediated Inhibition of Fungal Sterol Biosynthesis. J. Biol. Chem [print-electronic]. 2017 Mar 3/3/2017; PMID: 28258218, PII: M117.778308, DOI: 10.1074/jbc.M117.778308, ISSN: 1083-351X.
Guedes-da-Silva FH, Batista DG, Da Silva CF, De Araújo JS, Pavão BP, Simões-Silva MR, Meuser MB, Demarque KC, Moreira OC, Britto C, Lepesheva GI, Soeiro MN. Anti-trypanosomal activity of sterol 14a-demethylase (CYP51) inhibitors VNI and VFV in the Swiss mouse models of Chagas disease induced by the Y strain Trypanosoma cruzi. Antimicrob. Agents Chemother [print-electronic]. 2017 Feb 2/6/2017; PMID: 28167559, PII: AAC.02098-16, DOI: 10.1128/AAC.02098-16, ISSN: 1098-6596.
Hargrove TY, Friggeri L, Wawrzak Z, Sivakumaran S, Yazlovitskaya EM, Hiebert SW, Guengerich FP, Waterman MR, Lepesheva GI. Human sterol 14a-demethylase (CYP51) as a target for anticancer chemotherapy: Towards structure-aided drug design. J. Lipid Res [print-electronic]. 2016 Jun 6/16/2016; PMID: 27313059, PII: jlr.M069229, DOI: 10.1194/jlr.M069229, ISSN: 1539-7262.
Yu X, Nandekar P, Mustafa G, Cojocaru V, Lepesheva GI, Wade RC. Ligand tunnels in T. brucei and human CYP51: Insights for parasite-specific drug design. Biochim. Biophys. Acta [print-electronic]. 2016 Jan; 1860(1 Pt A): 67-78. PMID: 26493722, PMCID: PMC4689311, PII: S0304-4165(15)00287-1, DOI: 10.1016/j.bbagen.2015.10.015, ISSN: 0006-3002.
Hoekstra WJ, Hargrove TY, Wawrzak Z, Batista DD, da Silva CF, Nefertiti AS, Rachakonda G, Schotzinger RJ, Villalta F, Soeiro MN, Lepesheva GI. Antiparasitic effect in vitro, activity in a murine model of Chagas disease, and structural characterization in complex with the target enzyme CYP51 from Trypanosoma cruzi of the potent clinical candidate VT-1161. Antimicrob. Agents Chemother. 2015 Dec 12/7/2015; 60(2): 1058-66. PMID: 26643331, PII: AAC.02287-15, DOI: 10.1128/AAC.02287-15, ISSN: 1098-6596.
Guedes-da-Silva FH, Batista DG, da Silva CF, Meuser MB, Simões-Silva MR, de Araújo JS, Ferreira CG, Moreira OC, Britto C, Lepesheva GI, Soeiro Mde N. Different Therapeutic Outcomes of Benznidazole and VNI Treatments in Different Genders in Mouse Experimental Models of Trypanosoma cruzi Infection. Antimicrob. Agents Chemother [print-electronic]. 2015 Dec; 59(12): 7564-70. PMID: 26416857, PMCID: PMC4649169, PII: AAC.01294-15, DOI: 10.1128/AAC.01294-15, ISSN: 1098-6596.
Lepesheva GI, Hargrove TY, Rachakonda G, Wawrzak Z, Pomel S, Cojean S, Nde PN, Nes WD, Locuson CW, Calcutt MW, Waterman MR, Daniels JS, Loiseau PM, Villalta F. VFV as a New Effective CYP51 Structure-Derived Drug Candidate for Chagas Disease and Visceral Leishmaniasis. J. Infect. Dis [print-electronic]. 2015 Nov 11/1/2015; 212(9): 1439-48. PMID: 25883390, PMCID: PMC4601915, PII: jiv228, DOI: 10.1093/infdis/jiv228, ISSN: 1537-6613.
Hargrove TY, Wawrzak Z, Lamb DC, Guengerich FP, Lepesheva GI. Structure-Functional Characterization of Cytochrome P450 Sterol 14a-Demethylase (CYP51B) from Aspergillus fumigatus and Molecular Basis for the Development of Antifungal Drugs. J. Biol. Chem [print-electronic]. 2015 Sep 9/25/2015; 290(39): 23916-34. PMID: 26269599, PMCID: PMC4583043, PII: M115.677310, DOI: 10.1074/jbc.M115.677310, ISSN: 1083-351X.
Papadopoulou MV, Bloomer WD, Lepesheva GI, Rosenzweig HS, Kaiser M, Aguilera-Venegas B, Wilkinson SR, Chatelain E, Ioset JR. Novel 3-nitrotriazole-based amides and carbinols as bifunctional antichagasic agents. J. Med. Chem [print-electronic]. 2015 Feb 2/12/2015; 58(3): 1307-19. PMID: 25580906, PMCID: PMC4337820, DOI: 10.1021/jm5015742, ISSN: 1520-4804.
Yu X, Cojocaru V, Mustafa G, Salo-Ahen OM, Lepesheva GI, Wade RC. Dynamics of CYP51: implications for function and inhibitor design. J. Mol. Recognit [print-electronic]. 2015 Feb; 28(2): 59-73. PMID: 25601796, PMCID: PMC4337246, DOI: 10.1002/jmr.2412, ISSN: 1099-1352.
Cherkesova TS, Hargrove TY, Vanrell MC, Ges I, Usanov SA, Romano PS, Lepesheva GI. Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition. FEBS Lett [print-electronic]. 2014 Nov 11/3/2014; 588(21): 3878-85. PMID: 25217832, PMCID: PMC4252588, PII: S0014-5793(14)00657-7, DOI: 10.1016/j.febslet.2014.08.030, ISSN: 1873-3468.
Friggeri L, Hargrove TY, Rachakonda G, Williams AD, Wawrzak Z, Di Santo R, De Vita D, Waterman MR, Tortorella S, Villalta F, Lepesheva GI. Structural basis for rational design of inhibitors targeting Trypanosoma cruzi sterol 14a-demethylase: two regions of the enzyme molecule potentiate its inhibition. J. Med. Chem [print-electronic]. 2014 Aug 8/14/2014; 57(15): 6704-17. PMID: 25033013, PMCID: PMC4136671, DOI: 10.1021/jm500739f, ISSN: 1520-4804.
Lepesheva GI. Design or screening of drugs for the treatment of Chagas disease: what shows the most promise?. Expert Opin Drug Discov [print-electronic]. 2013 Dec; 8(12): 1479-89. PMID: 24079515, PMCID: PMC3867292, DOI: 10.1517/17460441.2013.845554, ISSN: 1746-045X.
Suryadevara PK, Racherla KK, Olepu S, Norcross NR, Tatipaka HB, Arif JA, Planer JD, Lepesheva GI, Verlinde CL, Buckner FS, Gelb MH. Dialkylimidazole inhibitors of Trypanosoma cruzi sterol 14a-demethylase as anti-Chagas disease agents. Bioorg. Med. Chem. Lett [print-electronic]. 2013 Dec 12/1/2013; 23(23): 6492-9. PMID: 24120539, PMCID: PMC4111244, PII: S0960-894X(13)00944-X, DOI: 10.1016/j.bmcl.2013.08.015, ISSN: 1464-3405.
Hargrove TY, Wawrzak Z, Alexander PW, Chaplin JH, Keenan M, Charman SA, Perez CJ, Waterman MR, Chatelain E, Lepesheva GI. Complexes of Trypanosoma cruzi sterol 14a-demethylase (CYP51) with two pyridine-based drug candidates for Chagas disease: structural basis for pathogen selectivity. J. Biol. Chem [print-electronic]. 2013 Nov 11/1/2013; 288(44): 31602-15. PMID: 24047900, PMCID: PMC3814756, PII: M113.497990, DOI: 10.1074/jbc.M113.497990, ISSN: 1083-351X.
Soeiro Mde N, de Souza EM, da Silva CF, Batista Dda G, Batista MM, Pavão BP, Araújo JS, Aiub CA, da Silva PB, Lionel J, Britto C, Kim K, Sulikowski G, Hargrove TY, Waterman MR, Lepesheva GI. In vitro and in vivo studies of the antiparasitic activity of sterol 14a-demethylase (CYP51) inhibitor VNI against drug-resistant strains of Trypanosoma cruzi. Antimicrob. Agents Chemother [print-electronic]. 2013 Sep; 57(9): 4151-63. PMID: 23774435, PMCID: PMC3754355, PII: AAC.00070-13, DOI: 10.1128/AAC.00070-13, ISSN: 1098-6596.
Villalta F, Dobish MC, Nde PN, Kleshchenko YY, Hargrove TY, Johnson CA, Waterman MR, Johnston JN, Lepesheva GI. VNI cures acute and chronic experimental Chagas disease. J. Infect. Dis [print-electronic]. 2013 Aug 8/1/2013; 208(3): 504-11. PMID: 23372180, PMCID: PMC3698996, PII: jit042, DOI: 10.1093/infdis/jit042, ISSN: 1537-6613.
Andriani G, Amata E, Beatty J, Clements Z, Coffey BJ, Courtemanche G, Devine W, Erath J, Juda CE, Wawrzak Z, Wood JT, Lepesheva GI, Rodriguez A, Pollastri MP. Antitrypanosomal lead discovery: identification of a ligand-efficient inhibitor of Trypanosoma cruzi CYP51 and parasite growth. J. Med. Chem [print-electronic]. 2013 Mar 3/28/2013; 56(6): 2556-67. PMID: 23448316, PMCID: PMC3612894, DOI: 10.1021/jm400012e, ISSN: 1520-4804.
Dobish MC, Villalta F, Waterman MR, Lepesheva GI, Johnston JN. Organocatalytic, enantioselective synthesis of VNI: a robust therapeutic development platform for Chagas, a neglected tropical disease. Org. Lett [print-electronic]. 2012 Dec 12/21/2012; 14(24): 6322-5. PMID: 23214987, PMCID: PMC3528807, DOI: 10.1021/ol303092v, ISSN: 1523-7052.
Hargrove TY, Kim K, de Nazaré Correia Soeiro M, da Silva CF, Batista DD, Batista MM, Yazlovitskaya EM, Waterman MR, Sulikowski GA, Lepesheva GI. CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds. Int J Parasitol Drugs Drug Resist [print-electronic]. 2012 Dec; 2: 178-86. PMID: 23504044, PMCID: PMC3596085, ISSN: 2211-3207.
Buckner FS, Bahia MT, Suryadevara PK, White KL, Shackleford DM, Chennamaneni NK, Hulverson MA, Laydbak JU, Chatelain E, Scandale I, Verlinde CL, Charman SA, Lepesheva GI, Gelb MH. Pharmacological characterization, structural studies, and in vivo activities of anti-Chagas disease lead compounds derived from tipifarnib. Antimicrob. Agents Chemother [print-electronic]. 2012 Sep; 56(9): 4914-21. PMID: 22777048, PMCID: PMC3421879, PII: AAC.06244-11, DOI: 10.1128/AAC.06244-11, ISSN: 1098-6596.
Nes CR, Singha UK, Liu J, Ganapathy K, Villalta F, Waterman MR, Lepesheva GI, Chaudhuri M, Nes WD. Novel sterol metabolic network of Trypanosoma brucei procyclic and bloodstream forms. Biochem. J. 2012 Apr 4/1/2012; 443(1): 267-77. PMID: 22176028, PMCID: PMC3491665, PII: BJ20111849, DOI: 10.1042/BJ20111849, ISSN: 1470-8728.
Hargrove TY, Wawrzak Z, Liu J, Waterman MR, Nes WD, Lepesheva GI. Structural complex of sterol 14a-demethylase (CYP51) with 14a-methylenecyclopropyl-Delta7-24, 25-dihydrolanosterol. J. Lipid Res [print-electronic]. 2012 Feb; 53(2): 311-20. PMID: 22135275, PMCID: PMC3269163, PII: jlr.M021865, DOI: 10.1194/jlr.M021865, ISSN: 0022-2275.
Hargrove TY, Wawrzak Z, Liu J, Nes WD, Waterman MR, Lepesheva GI. Substrate preferences and catalytic parameters determined by structural characteristics of sterol 14alpha-demethylase (CYP51) from Leishmania infantum. J. Biol. Chem [print-electronic]. 2011 Jul 7/29/2011; 286(30): 26838-48. PMID: 21632531, PMCID: PMC3143644, PII: M111.237099, DOI: 10.1074/jbc.M111.237099, ISSN: 1083-351X.
Lepesheva GI, Villalta F, Waterman MR. Targeting Trypanosoma cruzi sterol 14a-demethylase (CYP51). Adv. Parasitol. 2011; 75: 65-87. PMID: 21820552, PMCID: PMC3488290, PII: B978-0-12-385863-4.00004-6, DOI: 10.1016/B978-0-12-385863-4.00004-6, ISSN: 0065-308X.
Lepesheva GI, Waterman MR. Sterol 14alpha-demethylase (CYP51) as a therapeutic target for human trypanosomiasis and leishmaniasis. Curr Top Med Chem. 2011; 11(16): 2060-71. PMID: 21619513, PMCID: PMC3391166, PII: BSP/CTMC/E-Pub/-000127-11-16a, ISSN: 1873-4294.
Lepesheva GI, Waterman MR. Structural basis for conservation in the CYP51 family. Biochim. Biophys. Acta [print-electronic]. 2011 Jan; 1814(1): 88-93. PMID: 20547249, PMCID: PMC2962772, PII: S1570-9639(10)00164-0, DOI: 10.1016/j.bbapap.2010.06.006, ISSN: 0006-3002.
Lepesheva GI, Hargrove TY, Anderson S, Kleshchenko Y, Furtak V, Wawrzak Z, Villalta F, Waterman MR. Structural insights into inhibition of sterol 14alpha-demethylase in the human pathogen Trypanosoma cruzi. J. Biol. Chem [print-electronic]. 2010 Aug 8/13/2010; 285(33): 25582-90. PMID: 20530488, PMCID: PMC2919122, PII: M110.133215, DOI: 10.1074/jbc.M110.133215, ISSN: 1083-351X.
Lepesheva GI, Park HW, Hargrove TY, Vanhollebeke B, Wawrzak Z, Harp JM, Sundaramoorthy M, Nes WD, Pays E, Chaudhuri M, Villalta F, Waterman MR. Crystal structures of Trypanosoma brucei sterol 14alpha-demethylase and implications for selective treatment of human infections. J. Biol. Chem [print-electronic]. 2010 Jan 1/15/2010; 285(3): 1773-80. PMID: 19923211, PMCID: PMC2804335, PII: M109.067470, DOI: 10.1074/jbc.M109.067470, ISSN: 1083-351X.
Lamb DC, Lei L, Warrilow AG, Lepesheva GI, Mullins JG, Waterman MR, Kelly SL. The first virally encoded cytochrome p450. J. Virol [print-electronic]. 2009 Aug; 83(16): 8266-9. PMID: 19515774, PMCID: PMC2715754, PII: JVI.00289-09, DOI: 10.1128/JVI.00289-09, ISSN: 1098-5514.
Konkle ME, Hargrove TY, Kleshchenko YY, von Kries JP, Ridenour W, Uddin MJ, Caprioli RM, Marnett LJ, Nes WD, Villalta F, Waterman MR, Lepesheva GI. Indomethacin amides as a novel molecular scaffold for targeting Trypanosoma cruzi sterol 14alpha-demethylase. J. Med. Chem. 2009 May 5/14/2009; 52(9): 2846-53. PMID: 19354253, PMCID: PMC2744100, DOI: 10.1021/jm801643b, ISSN: 1520-4804.
Kraus JM, Verlinde CL, Karimi M, Lepesheva GI, Gelb MH, Buckner FS. Rational modification of a candidate cancer drug for use against Chagas disease. J. Med. Chem. 2009 Mar 3/26/2009; 52(6): 1639-47. PMID: 19239254, PMCID: PMC2715367, DOI: 10.1021/jm801313t, ISSN: 1520-4804.
Lepesheva GI, Hargrove TY, Kleshchenko Y, Nes WD, Villalta F, Waterman MR. CYP51: A major drug target in the cytochrome P450 superfamily. Lipids [print-electronic]. 2008 Dec; 43(12): 1117-25. PMID: 18769951, PMCID: PMC2715142, DOI: 10.1007/s11745-008-3225-y, ISSN: 0024-4201.
Lepesheva GI, Ott RD, Hargrove TY, Kleshchenko YY, Schuster I, Nes WD, Hill GC, Villalta F, Waterman MR. Sterol 14alpha-demethylase as a potential target for antitrypanosomal therapy: enzyme inhibition and parasite cell growth. Chem. Biol. 2007 Nov; 14(11): 1283-93. PMID: 18022567, PMCID: PMC2324070, PII: S1074-5521(07)00362-6, DOI: 10.1016/j.chembiol.2007.10.011, ISSN: 1074-5521.
Lepesheva GI, Seliskar M, Knutson CG, Stourman NV, Rozman D, Waterman MR. Conformational dynamics in the F/G segment of CYP51 from Mycobacterium tuberculosis monitored by FRET. Arch. Biochem. Biophys [print-electronic]. 2007 Aug 8/15/2007; 464(2): 221-7. PMID: 17585868, PMCID: PMC3042880, PII: S0003-9861(07)00271-8, DOI: 10.1016/j.abb.2007.05.017, ISSN: 0003-9861.
Lepesheva GI, Waterman MR. Sterol 14alpha-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms. Biochim. Biophys. Acta [print-electronic]. 2007 Mar; 1770(3): 467-77. PMID: 16963187, PMCID: PMC2324071, PII: S0304-4165(06)00214-5, DOI: 10.1016/j.bbagen.2006.07.018, ISSN: 0006-3002.
Lepesheva GI, Hargrove TY, Ott RD, Nes WD, Waterman MR. Biodiversity of CYP51 in trypanosomes. Biochem. Soc. Trans. 2006 Dec; 34(Pt 6): 1161-4. PMID: 17073776, PII: BST0341161, DOI: 10.1042/BST0341161, ISSN: 0300-5127.
Strushkevich NV, Harnastai IN, Lepesheva GI, Usanov SA. Role of C-terminal sequence of cytochrome P450scc in folding and functional activity. Biochemistry Mosc. 2006 Sep; 71(9): 1027-34. PMID: 17009958, PII: BCM71091269, ISSN: 0006-2979.
Zhou W, Lepesheva GI, Waterman MR, Nes WD. Mechanistic analysis of a multiple product sterol methyltransferase implicated in ergosterol biosynthesis in Trypanosoma brucei. J. Biol. Chem [print-electronic]. 2006 Mar 3/10/2006; 281(10): 6290-6. PMID: 16414960, PII: M511749200, DOI: 10.1074/jbc.M511749200, ISSN: 0021-9258.
Lepesheva GI, Zaitseva NG, Nes WD, Zhou W, Arase M, Liu J, Hill GC, Waterman MR. CYP51 from Trypanosoma cruzi: a phyla-specific residue in the B' helix defines substrate preferences of sterol 14alpha-demethylase. J. Biol. Chem [print-electronic]. 2006 Feb 2/10/2006; 281(6): 3577-85. PMID: 16321980, PII: M510317200, DOI: 10.1074/jbc.M510317200, ISSN: 0021-9258.
Lamb DC, Kim Y, Yermalitskaya LV, Yermalitsky VN, Lepesheva GI, Kelly SL, Waterman MR, Podust LM. A second FMN binding site in yeast NADPH-cytochrome P450 reductase suggests a mechanism of electron transfer by diflavin reductases. Structure. 2006 Jan; 14(1): 51-61. PMID: 16407065, PII: S0969-2126(05)00395-3, DOI: 10.1016/j.str.2005.09.015, ISSN: 0969-2126.
Waterman MR, Lepesheva GI. Sterol 14 alpha-demethylase, an abundant and essential mixed-function oxidase. Biochem. Biophys. Res. Commun [print-electronic]. 2005 Dec 12/9/2005; 338(1): 418-22. PMID: 16153595, PII: S0006-291X(05)01851-6, DOI: 10.1016/j.bbrc.2005.08.118, ISSN: 0006-291X.
Strushkevich NV, Azeva TN, Lepesheva GI, Usanov SA. Role of positively charged residues lys267, lys270, and arg411 of cytochrome p450scc (CYP11A1) in interaction with adrenodoxin. Biochemistry Mosc. 2005 Jun; 70(6): 664-71. PMID: 16038609, PII: BCM70060805, ISSN: 0006-2979.
Podust LM, Yermalitskaya LV, Lepesheva GI, Podust VN, Dalmasso EA, Waterman MR. Estriol bound and ligand-free structures of sterol 14alpha-demethylase. Structure. 2004 Nov; 12(11): 1937-45. PMID: 15530358, PII: S0969212604003363, DOI: 10.1016/j.str.2004.08.009, ISSN: 0969-2126.
Bellamine A, Lepesheva GI, Waterman MR. Fluconazole binding and sterol demethylation in three CYP51 isoforms indicate differences in active site topology. J. Lipid Res [print-electronic]. 2004 Nov; 45(11): 2000-7. PMID: 15314102, PII: M400239-JLR200, DOI: 10.1194/jlr.M400239-JLR200, ISSN: 0022-2275.
Lepesheva GI, Nes WD, Zhou W, Hill GC, Waterman MR. CYP51 from Trypanosoma brucei is obtusifoliol-specific. Biochemistry. 2004 Aug 8/24/2004; 43(33): 10789-99. PMID: 15311940, DOI: 10.1021/bi048967t, ISSN: 0006-2960.
Lepesheva GI, Waterman MR. CYP51--the omnipotent P450. Mol. Cell. Endocrinol. 2004 Feb 2/27/2004; 215(1-2): 165-70. PMID: 15026190, PII: S0303720703005148, DOI: 10.1016/j.mce.2003.11.016, ISSN: 0303-7207.
Lepesheva GI, Virus C, Waterman MR. Conservation in the CYP51 family. Role of the B' helix/BC loop and helices F and G in enzymatic function. Biochemistry. 2003 Aug 8/5/2003; 42(30): 9091-101. PMID: 12885242, DOI: 10.1021/bi034663f, ISSN: 0006-2960.
Usanov SA, Graham SE, Lepesheva GI, Azeva TN, Strushkevich NV, Gilep AA, Estabrook RW, Peterson JA. Probing the interaction of bovine cytochrome P450scc (CYP11A1) with adrenodoxin: evaluating site-directed mutations by molecular modeling. Biochemistry. 2002 Jul 7/2/2002; 41(26): 8310-20. PMID: 12081479, PII: bi0255928, ISSN: 0006-2960.
Lepesheva GI, Podust LM, Bellamine A, Waterman MR. Folding requirements are different between sterol 14alpha-demethylase (CYP51) from Mycobacterium tuberculosis and human or fungal orthologs. J. Biol. Chem [print-electronic]. 2001 Jul 7/27/2001; 276(30): 28413-20. PMID: 11373285, PII: M102767200, DOI: 10.1074/jbc.M102767200, ISSN: 0021-9258.
Azeva TN, Gilep AA, Lepesheva GI, Strushkevich NV, Usanov SA. Site-directed mutagenesis of cytochrome P450scc. II. Effect of replacement of the Arg425 and Arg426 residues on the structural and functional properties of the cytochrome P450scc. Biochemistry Mosc. 2001 May; 66(5): 564-75. PMID: 11405894, PII: BCM66050698, ISSN: 0006-2979.
Lepesheva GI, Azeva TN, Strushkevich NV, Gilep AA, Usanov SA. Site-directed mutagenesis of cytochrome P450scc (CYP11A1). Effect of lysine residue substitution on its structural and functional properties. Biochemistry Mosc. 2000 Dec; 65(12): 1409-18. PMID: 11173513, PII: BCM65121673, ISSN: 0006-2979.
Lepesheva GI, Strushkevich NV, Usanov SA. Conformational dynamics and molecular interaction reactions of recombinant cytochrome p450scc (CYP11A1) detected by fluorescence energy transfer. Biochim. Biophys. Acta. 1999 Sep 9/14/1999; 1434(1): 31-43. PMID: 10556557, PII: S0167-4838(99)00156-9, ISSN: 0006-3002.
Lepesheva GI, Azeva TN, Strushkevich NV, Adamovich TB, Cherkesova TS, Usanov SA. Comparative structural-functional characterization of recombinant and natural adrenodoxin. Interaction with cytochrome P450scc. Biochemistry Mosc. 1999 Sep; 64(9): 1079-88. PMID: 10521726, PII: BCM64091280, ISSN: 0006-2979.
Lepesheva GI, Usanov SA. Comparative structural and immunochemical characterization of recombinant and natural cytochrome p450scc (CYPXIAI). Biochemistry Mosc. 1998 Feb; 63(2): 224-34. PMID: 9526119, ISSN: 0006-2979.
Lepesheva GI, Usanov SA. Dynamics and functional activity of cytochrome P450scc selectively labeled with fluorescein isothiocyanate. Biochemistry Mosc. 1997 Jun; 62(6): 648-56. PMID: 9324423, ISSN: 0006-2979.
Lepesheva GI, Usanov SA. [The use of selective chemical modification of cytochrome P450scc (CYPXIA1) with fluorescein isothiocyanate for evaluation of intramolecular distances and conformational changes by fluorescent resonance energy transfer]. Biokhimiia. 1996 Aug; 61(8): 1395-407. PMID: 8962914, ISSN: 0320-9725.
Lepesheva GI, Turko IV, Ges' IA, Chashchin VL. [Direct detection of an antigen in immunoglobulin G Langmuir-Blodgett films based on a surface plasma resonance method and in a piezoelectric system]. Biokhimiia. 1994 Jul; 59(7): 939-45. PMID: 7948419, ISSN: 0320-9725.
Lepesheva GI, Turko IV, Shestakov VL, Chashchin VL. [IgG, modified with coproporphyrin I and the possibility of direct measurement of the antigen-antibody complex]. Biokhimiia. 1993 Jun; 58(6): 938-43. PMID: 8364116, ISSN: 0320-9725.
Lepesheva GI, Martsev SP. [Modification of a disulfide in the hinge region of rabbit IgG and study of the interaction of polyvalent ferritin antigen, protein A, and anti-IgG]. Biokhimiia. 1992 Jul; 57(7): 1089-99. PMID: 1391214, ISSN: 0320-9725.
Lepesheva GI, Martsev SP. [The use of biotin-streptavidin systems for enhancing the parameters of immunometric analysis]. Zh. Mikrobiol. Epidemiol. Immunobiol. 1990 Oct; (10): 121-5. PMID: 2075757, ISSN: 0372-9311.
A Requirement for an Active Proton Delivery Network Supports a Compound I Mediated C-C Bond Cleavage in CYP51 Catalysis. J. Biol.Chem.