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Lanosterol 14 alpha-demethylase
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<h2 id="evolution">Evolution</h2> <p class="note">Main article: <a href="/facts/CYP51/MF0pQ8fQ">CYP51</a></p> <p>The structural and functional properties of the <a href="/facts/Cytochrome_P450/alxusFD0">cytochrome P450</a> superfamily have been subject to extensive diversification over the course of evolution.<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> Recent estimates indicate that there are currently 10 <a href="/facts/Class_(biology)/a7MrgFu3">classes</a> and 267 <a href="/facts/Family_(biology)/qTrn6E8E">families</a> of CYP proteins.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> It is believed that 14α-demethylase or CYP51 diverged early in the cytochrome's <a href="/facts/Evolutionary_history/Ss6eB0EX">evolutionary history</a> and has preserved its function ever since; namely, the removal of the 14α-methyl group from sterol <a href="/facts/Substrate_(biochemistry)/6MnaV19h">substrates</a>.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> </p><p>Although CYP51's mode of action has been well <a href="/facts/Conserved_sequence/YAxy2Xa2">conserved</a>, the protein's sequence varies considerably between biological kingdoms.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> CYP51 sequence comparisons between kingdoms reveal only a 22-30% similarity in amino acid composition.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p> <h2 id="structure">Structure</h2> <p>Although the structure of 14α-demethylase may vary substantially from one organism to the next, <a href="/facts/Sequence_alignment/p8GQfF7b">sequence alignment</a> analysis reveals that there are six regions in the protein that are highly <a href="/facts/Conserved_sequence/YAxy2Xa2">conserved</a> in <a href="/facts/Eukaryotes/SkwyPLMA">eukaryotes</a>.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> These include residues in the B' helix, B'/C loop, C helix, I helix, K/β1-4 loop, and β-strand 1-4 that are responsible for forming the surface of the substrate binding cavity.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> <a href="/facts/Homology_modeling/rgaHkvJX">Homology modeling</a> reveals that <a href="/facts/Substrate_(biochemistry)/6MnaV19h">substrates</a> migrate from the surface of the protein to the enzyme's buried <a href="/facts/Active_site/u9ua7rGu">active site</a> through a channel that is formed in part by the A' <a href="/facts/Alpha_helix/7CESPIYJ">alpha helix</a> and the β4 loop.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a><a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> Finally, the <a href="/facts/Active_site/u9ua7rGu">active site</a> contains a <a href="/facts/Heme/fRhyJAAb">heme</a> <a href="/facts/Prosthetic_group/XnFupodh">prosthetic group</a> in which the iron is tethered to the sulfur atom on a conserved cysteine residue.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> This group also binds diatomic oxygen at the sixth coordination site, which is eventually incorporated onto the substrate.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> </p> <h2 id="mechanism">Mechanism</h2> <p>The enzyme-catalyzed <a href="/facts/Demethylation/AvM5BLjD">demethylation</a> of <a href="/facts/Lanosterol/nmuMgCK3">lanosterol</a> is believed to occur in three steps, each of which requires one molecule of diatomic oxygen and one molecule of <a href="/facts/NADPH/XMgmPQ5t">NADPH</a> (or some other <a href="/facts/Reducing_equivalent/yE5ukPx6">reducing equivalent</a>).<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> During the first two steps, the 14α-methyl group undergoes typical <a href="/facts/Cytochrome_P450/alxusFD0">cytochrome</a> monooxygenation in which one oxygen atom is incorporated by the substrate and the other is reduced to water, resulting in the sterol's conversion to a carboxyalcohol and then a carboxyaldehyde.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> The aldehyde then departs as <a href="/facts/Formic_acid/o6cFsbNc">formic acid</a> and a double bond is simultaneously introduced to yield the demethylated product.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Steroidogenic_enzyme/zfzah2tq">Steroidogenic enzyme</a></li> <li><a href="/facts/Azole_antifungals/Nj3CWSM2">Azole antifungals</a></li></ul> <h2 id="further-reading">Further reading</h2> <ul><li>Bak S, Kahn RA, Olsen CE, Halkier BA (February 1997). <a href="https://doi.org/10.1046%2Fj.1365-313X.1997.11020191.x">"Cloning and expression in Escherichia coli of the obtusifoliol 14 alpha-demethylase of Sorghum bicolor (L.) Moench, a cytochrome P450 orthologous to the sterol 14 alpha-demethylases (CYP51) from fungi and mammals"</a>. <i>The Plant Journal</i>. 11 (2): 191–201. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1046%2Fj.1365-313X.1997.11020191.x">10.1046/j.1365-313X.1997.11020191.x</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9076987">9076987</a>.</li> <li>Aoyama Y, Yoshida Y (August 1991). "Different substrate specificities of lanosterol 14a-demethylase (P-45014DM) of Saccharomyces cerevisiae and rat liver for 24-methylene-24,25-dihydrolanosterol and 24,25-dihydrolanosterol". <i>Biochemical and Biophysical Research Communications</i>. 178 (3): 1064–71. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2F0006-291X%2891%2991000-3">10.1016/0006-291X(91)91000-3</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/1872829">1872829</a>.</li> <li>Aoyama Y, Yoshida Y (March 1992). "The 4 beta-methyl group of substrate does not affect the activity of lanosterol 14 alpha-demethylase (P-450(14)DM) of yeast: difference between the substrate recognition by yeast and plant sterol 14 alpha-demethylases". <i>Biochemical and Biophysical Research Communications</i>. 183 (3): 1266–72. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS0006-291X%2805%2980327-4">10.1016/S0006-291X(05)80327-4</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/1567403">1567403</a>.</li> <li>Alexander K, Akhtar M, Boar RB, McGhie JF, Barton DH (1972). "The removal of the 32-carbon atom as formic acid in cholesterol biosynthesis". <i>Journal of the Chemical Society, Chemical Communications</i> (7): 383. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1039%2FC39720000383">10.1039/C39720000383</a>.</li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://meshb.nlm.nih.gov/record/ui?name=cytochrome+P-450+CYP51">cytochrome+P-450+CYP51</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>"Metabocard for 4,4-Dimethylcholesta-8,14,24-trienol (HMDB01023)". Human Metabolome Database. February 2014. <a href="http://www.hmdb.ca/metabolites/HMDB01023" target="_blank">http://www.hmdb.ca/metabolites/HMDB01023</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Lepesheva GI, Waterman MR (March 2007). "Sterol 14alpha-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms". Biochimica et Biophysica Acta (BBA) - General Subjects. 1770 (3): 467–77. doi:10.1016/j.bbagen.2006.07.018. PMC 2324071. PMID 16963187. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2324071" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2324071</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Lepesheva GI, Waterman MR (March 2007). "Sterol 14alpha-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms". Biochimica et Biophysica Acta (BBA) - General Subjects. 1770 (3): 467–77. doi:10.1016/j.bbagen.2006.07.018. PMC 2324071. PMID 16963187. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2324071" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2324071</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Lepesheva GI, Waterman MR (March 2007). "Sterol 14alpha-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms". Biochimica et Biophysica Acta (BBA) - General Subjects. 1770 (3): 467–77. doi:10.1016/j.bbagen.2006.07.018. PMC 2324071. PMID 16963187. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2324071" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2324071</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Becher R, Wirsel SG (August 2012). "Fungal cytochrome P450 sterol 14α-demethylase (CYP51) and azole resistance in plant and human pathogens". Applied Microbiology and Biotechnology. 95 (4): 825–40. doi:10.1007/s00253-012-4195-9. PMID 22684327. S2CID 17688962. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Hannemann F, Bichet A, Ewen KM, Bernhardt R (March 2007). "Cytochrome P450 systems--biological variations of electron transport chains". Biochimica et Biophysica Acta (BBA) - General Subjects. 1770 (3): 330–44. doi:10.1016/j.bbagen.2006.07.017. PMID 16978787. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Becher R, Wirsel SG (August 2012). "Fungal cytochrome P450 sterol 14α-demethylase (CYP51) and azole resistance in plant and human pathogens". Applied Microbiology and Biotechnology. 95 (4): 825–40. doi:10.1007/s00253-012-4195-9. PMID 22684327. S2CID 17688962. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Lepesheva GI, Waterman MR (February 2004). "CYP51--the omnipotent P450". Molecular and Cellular Endocrinology. 215 (1–2): 165–70. doi:10.1016/j.mce.2003.11.016. PMID 15026190. S2CID 22489096. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Lepesheva GI, Waterman MR (January 2011). "Structural basis for conservation in the CYP51 family". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1814 (1): 88–93. doi:10.1016/j.bbapap.2010.06.006. PMC 2962772. PMID 20547249. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962772" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962772</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Lepesheva GI, Waterman MR (January 2011). "Structural basis for conservation in the CYP51 family". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1814 (1): 88–93. doi:10.1016/j.bbapap.2010.06.006. PMC 2962772. PMID 20547249. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962772" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962772</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Becher R, Wirsel SG (August 2012). "Fungal cytochrome P450 sterol 14α-demethylase (CYP51) and azole resistance in plant and human pathogens". Applied Microbiology and Biotechnology. 95 (4): 825–40. doi:10.1007/s00253-012-4195-9. PMID 22684327. S2CID 17688962. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Hargrove TY, Wawrzak Z, Liu J, Nes WD, Waterman MR, Lepesheva GI (July 2011). "Substrate preferences and catalytic parameters determined by structural characteristics of sterol 14alpha-demethylase (CYP51) from Leishmania infantum". The Journal of Biological Chemistry. 286 (30): 26838–48. doi:10.1074/jbc.M111.237099. PMC 3143644. PMID 21632531. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143644" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143644</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Podust LM, von Kries JP, Eddine AN, Kim Y, Yermalitskaya LV, Kuehne R, et al. (November 2007). "Small-molecule scaffolds for CYP51 inhibitors identified by high-throughput screening and defined by X-ray crystallography". Antimicrobial Agents and Chemotherapy. 51 (11): 3915–23. doi:10.1128/AAC.00311-07. PMC 2151439. PMID 17846131. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151439" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151439</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Lepesheva GI, Waterman MR (January 2011). "Structural basis for conservation in the CYP51 family". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1814 (1): 88–93. doi:10.1016/j.bbapap.2010.06.006. PMC 2962772. PMID 20547249. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962772" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962772</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Lepesheva GI, Waterman MR (January 2011). "Structural basis for conservation in the CYP51 family". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1814 (1): 88–93. doi:10.1016/j.bbapap.2010.06.006. PMC 2962772. PMID 20547249. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962772" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962772</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>Vanden Bossche H, Koymans L (1998). "Cytochromes P450 in fungi". Mycoses. 41 (Suppl 1): 32–8. doi:10.1111/j.1439-0507.1998.tb00581.x. PMID 9717384. S2CID 83821510. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>Lepesheva GI, Waterman MR (January 2011). "Structural basis for conservation in the CYP51 family". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1814 (1): 88–93. doi:10.1016/j.bbapap.2010.06.006. PMC 2962772. PMID 20547249. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962772" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962772</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> <li id="fn:18"><p>Lepesheva GI, Waterman MR (January 2011). "Structural basis for conservation in the CYP51 family". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1814 (1): 88–93. doi:10.1016/j.bbapap.2010.06.006. PMC 2962772. PMID 20547249. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962772" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962772</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></p></li> </ol>