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Strushkevich N.,University of Toronto | Usanov S.A.,Institute of Bioorganic Chemistry NASB | Park H.-W.,University of Toronto | Park H.-W.,Kings College
Journal of Molecular Biology | Year: 2010

The obligatory step in sterol biosynthesis in eukaryotes is demethylation of sterol precursors at the C14-position, which is catalyzed by CYP51 (sterol 14-alpha demethylase) in three sequential reactions. In mammals, the final product of the pathway is cholesterol, while important intermediates, meiosis-activating sterols, are produced by CYP51. Three crystal structures of human CYP51, ligand-free and complexed with antifungal drugs ketoconazole and econazole, were determined, allowing analysis of the molecular basis for functional conservation within the CYP51 family. Azole binding occurs mostly through hydrophobic interactions with conservative residues of the active site. The substantial conformational changes in the B′ helix and F-G loop regions are induced upon ligand binding, consistent with the membrane nature of the protein and its substrate. The access channel is typical for mammalian sterol-metabolizing P450 enzymes, but is different from that observed in Mycobacterium tuberculosis CYP51. Comparison of the azole-bound structures provides insight into the relative binding affinities of human and bacterial P450 enzymes to ketoconazole and fluconazole, which can be useful for the rational design of antifungal compounds and specific modulators of human CYP51. © 2010 Elsevier Ltd.


Yuvs G.G.,Laboratory of Spectroscopic Research Spektrum Ltd | Ignatova T.N.,Laboratory of Spectroscopic Research Spektrum Ltd | Anuchin A.M.,Laboratory of Spectroscopic Research Spektrum Ltd | Lebedeva V.L.,Lyubertsy District Hospital 2 | And 2 more authors.
Voprosy Pitaniia | Year: 2015

Elemental status of a person determines the qualitative and quantitative content of chemical elements in the human body. This marker allows us to estimate the level of imbalance of chemical elements and therefore health risks. The method for simultaneous quantitative and qualitative analysis of 67 elements in biomaterials has been proposed. The detailed elemental analysis of whole blood samples of 1711 healthy people (age range 0-100 years) of Moscow Region has been performed. A number of patterns of age-related changes of the element status conditionally healthy people has been estimated. Na content in the samples increased with the age of the person. Presumably, this result reflects the studied populations nutrition disorders associated with immoderate consumption of table salt. The maximum content of Ca was observed in blood samples of people age range 0-20 years (66-69 mg/kg), the Ca content in the blood samples of people age range 26-85 years was significantly lower (59-62 mg/kg). The maximum decrease of Ca was detected in blood samples of people age range of 85-100 years (57-59 mg/kg). This reduction in the concentration of Ca, apparently due to age-related changes of Ca balance, correlates with decrease of bone mineral density and bone mass. Iron content decreased in the blood samples of people age range 10-100 years from 480 to 390 mg/kg. Selenium content in blood of people age range 0-25 years linearly increased, remained stable high in the blood of people age range 25-55 years (0, 13-0, 136 mg/kg) and then gradually decreased. A graph of As content dependence from a person's age is a mirror image of the graph of Se content dependence from a person's age, which is evidence of the antagonistic effects of these elements. Graphic changes in the content of rare earth elements Eu and Ho reflect the unidirectional trend of these elements accumulation. The maximum content of these elements was observed in blood samples of people age range of 25-65 years. Perhaps a reduction of Eu and Ho in the age range 65-100 years age reflects a downward trend in bone mineral density and decrease in bone mass, which correlates with the Ca content in the blood depending on the age of people. The data obtained showed a significant increase of U and V in the blood of people age range of 85-100 years. The compounds of vanadium and uranium normally relatively easily filtered by the kidneys and excreted in the urine. This result seems to demonstrate age-related deterioration in the functioning of the excretory system. A list of recommendations f or nutrition correction of elemental imbalance of the observed population has been proposed.


Gilep A.A.,Institute of Bioorganic Chemistry NASB | Sushko T.A.,Institute of Bioorganic Chemistry NASB | Usanov S.A.,Institute of Bioorganic Chemistry NASB
Biochimica et Biophysica Acta - Proteins and Proteomics | Year: 2011

Cytochrome P450s play critical roles in the metabolism of various bioactive compounds. One of the crucial functions of cytochrome P450s in Chordata is in the biosynthesis of steroid hormones. Steroid 17alpha-hydroxylase/17,20-lyase (CYP17) is localized in endoplasmic reticulum membranes of steroidogenic cells. CYP17 catalyzes the 17alpha-hydroxylation reaction of delta4-C21 steroids (progesterone derivatives) and delta5-C21 steroids (pregnenolone derivatives) as well as the 17,20-lyase reaction producing C 19-steroids, a key branch point in steroid hormone biosynthesis. Depending on CYP17 activity, the steroid hormone biosynthesis pathway is directed to either the formation of mineralocorticoids and glucocorticoids or sex hormones. In the present review, the current information on CYP17 is analyzed and discussed. © 2010 Elsevier B.V. All rights reserved.


Sushko T.A.,Institute of Bioorganic Chemistry NASB | Gilep A.A.,Institute of Bioorganic Chemistry NASB | Usanov S.A.,Institute of Bioorganic Chemistry NASB
Anti-Cancer Agents in Medicinal Chemistry | Year: 2014

Most prostate and breast cancers are hormone dependent. The inhibition of steroid 17α-hydroxylase/17,20- lyase (CYP17), which is a crucial enzyme for steroid hormone biosynthesis, is widely used to treat androgen-dependent prostate cancer (PC). CYP17 has dual enzymatic activity: 17alpha-hydroxylase activity (utilizing delta4- C21 steroids as substrates) and the 17,20-lyase activity (using delta5- C21 steroids as substrates). The steroid biosynthetic pathway is directed to either the production of corticosteroids or sex hormones depending on the activity of CYP17. In this review, the current information on the genetics, molecular structure, substrate specificity and inhibitors of CYP17 is analyzed and discussed. © 2014 Bentham Science Publishers.

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