a 3-oxo-5α-steroid + acceptor ⇌ a 3-oxo-Δ4-steroid + reduced acceptor
Where a 3-oxo-5α-steroid and acceptor are substrates, and a corresponding 3-oxo-Δ4-steroid and the reduced acceptor are products. An instance of this generalized reaction that 5α-reductase type 2 catalyzes is:
5α-Reductases act on 3-oxo (3-keto), Δ4,5 C19/C21 steroids as its substrates; "3-keto" refers to the double bond of the third carbon to oxygen. Carbons 4 and 5 also have a double bond, represented by 'Δ4,5'. The reaction involves a stereospecific and permanent break of the Δ4,5 with the help of NADPH as a cofactor. A hydride anion (H−) is also placed on the α face at the fifth carbon, and a proton on the β face at carbon 4.[8]
Distribution with age
5α-R1 is expressed in fetal scalp and nongenital skin of the back, anywhere from 5 to 50 times less than in the adult. 5α-R2 is expressed in fetal prostates similar to adults. 5α-R1 is expressed mainly in the epithelium and 5α-R2 the stroma of the fetal prostate. Scientists looked for 5α-R2 expression in fetal liver, adrenal, testis, ovary, brain, scalp, chest, and genital skin, using immunoblotting, and were only able to find it in genital skin.[8]
After birth, the 5α-R1 is expressed in more locations, including the liver, skin, scalp and prostate. 5α-R2 is expressed in prostate, seminal vesicles, epididymis, liver, and to a lesser extent the scalp and skin. Hepatic expression of both 5α-R1 and 2 is immediate, but disappears in the skin and scalp at month 18. Then, at puberty, only 5α-R2 is reexpressed in the skin and scalp.
5α-R1 and 5α-R2 appear to be expressed in the prostate in male fetuses and throughout postnatal life. 5α-R1 and 5α-R2 are also expressed, although to different degrees in liver, genital and nongenital skin, prostate, epididymis, seminal vesicle, testis, ovary, uterus, kidney, exocrine pancreas, and the brain.[3][8]
Specific substrates include testosterone, progesterone, androstenedione,[9]epitestosterone, cortisol, aldosterone, and deoxycorticosterone. Outside of dihydrotestosterone, much of the physiological role of 5α-reduced steroids is unknown.[8] Beyond reducing testosterone to dihydrotestosterone, 5alpha-reductase enzyme isoforms I and II reduce progesterone to dihydroprogesterone (DHP) and deoxycorticosterone to dihydrodeoxycorticosterone (DHDOC). In vitro and animal models suggest subsequent 3alpha-reduction of DHT, DHP and DHDOC lead to steroid metabolites with effects on cerebral function achieved by enhancing GABAergic inhibition. These neuroactive steroid derivatives enhance GABA via allosteric modulation at GABA(A) receptors and have anticonvulsant, antidepressant and anxiolytic effects, and also alter sexual and alcohol related behavior.[10] 5α-dihydrocortisol is present in the aqueous humor of the eye, is synthesized in the lens, and might help make the aqueous humor itself.[11]Allopregnanolone and THDOC are neurosteroids, with the latter having effects on the susceptibility of animals to seizures. In socially isolated mice, 5α-R1 is specifically down-regulated in glutamatergic pyramidal neurons that converge on the amygdala from cortical and hippocampal regions. This down-regulation may account for the appearance of behavioral disorders such as anxiety, aggression, and cognitive dysfunction.[3][4] 5α-dihydroaldosterone is a potent antinatriuretic agent, although different from aldosterone. Its formation in the kidney is enhanced by restriction of dietary salt, suggesting it may help retain sodium as follows:[12]
5α-DHP is a major hormone in circulation of normal cycling and pregnant women.[14]
5α-Reductase is a membrane bound enzyme that catalyzes the NADPH dependent reduction of double bonds in steroid substrates to increase potency.[15] The crystal structure of a homolog of 5α-reductase isoenzymes 1 and 2 has been found in Proteobacteria (proteobacteria 5α-reductase). This exists as a monomer with a seven alpha-helix transmembrane structure housing a hydrophobic pocket that holds cofactor NADPH and monoolein which occupies the steroid substrate binding pocket.[16] In insect cells monoolein is not found, but is subbed out for other androgens and inhibitors.[17] The integral seven transmembrane topology is likely conserved across species, with the N terminus in the endoplasmic reticulum lumen and the C terminus facing the cytosol. High conformational dynamics of the cytosolic region likely regulate NADPH/NADP+ exchange.[17]Sequence conservation across known crystal structures has corroborated high conservation in enzyme structure.[16]
Inhibition of the enzyme can be classified into two categories: steroidal, which are irreversible, and nonsteroidal. There are more steroidal inhibitors, with examples including finasteride (MK-906), dutasteride (GG745), 4-MA, turosteride, MK-386, MK-434, and MK-963. Researchers have pursued synthesis of nonsteroidals to inhibit 5α-reductase due to the undesired side effects of steroidals. The most potent and selective inhibitors of 5α-R1 are found in this class, and include benzoquinolones, nonsteroidal aryl acids, butanoic acid derivatives, and more recognizably, polyunsaturated fatty acids (especially linolenic acid), zinc, and green tea.[8]Riboflavin was also identified as a 5α-reductase inhibitor .[18]
Gynecomastia, erectile dysfunction, impaired cognitive function, fatigue, hypoglycemia, impaired liver function, constipation, and depression, are only a few of the possible side-effects of 5α-reductase inhibition. Long term side effects, that continued even after discontinuation of the drug have been reported.[20]
Finasteride
Finasteride inhibits two 5α-reductase isoenzymes (II and III), while dutasteride inhibits all three.[2] Finasteride potently inhibits 5α-R2 at a mean inhibitory concentration IC50 of 69 nM, but is less effective with 5α-R1 with an IC50 of 360 nM.[21] Finasteride decreases mean serum level of DHT by 71% after 6 months,[22] and was shown in vitro to inhibit 5α-R3 at a similar potency to 5α-R2 in transfected cell lines.[2]
Dutasteride
Dutasteride inhibits 5α-reductase isoenzymes type 1 and 2 better than finasteride, leading to a more complete reduction in DHT at 24 weeks (94.7% versus 70.8%).[23] It also reduces intraprostatic DHT 97% in men with prostate cancer at 5 mg/day over three months.[24] A second study with 3.5 mg/day for 4 months decreased intraprostatic DHT even further by 99%.[25] The suppression of DHT in vivo, and the report that dutasteride inhibits 5α-R3 in vitro[26] suggest that dutasteride may be a triple 5α reductase inhibitor.[8]
5α-Reductase type 1 inactivated male mice have reduced bone mass and forelimb muscle grip strength, which has been proposed to be due to lack of 5α-reductase type 1 expression in bone and muscle.[29] In 5 alpha reductase type 2 deficient males, the type 1 isoenzyme is thought to be responsible for their virilization at puberty.[6]
5α-Reductase 2
Impaired 5α-reductase 2 activity can result from mutations in the underlying SRD5A2 gene. The condition, known as 5α-reductase 2 deficiency, has a range of presentations as atypical appearances of the external genitalia in males. This is because 5α-reductase 2 catalyzes the transformation of testosterone to the potent androgen dihydrotestosterone, which is required for the proper masculinization of male genitalia.[30]
5α-Reductase 3
When small interfering RNA is used to knock down the expression of 5α-R3 isozyme in cell lines, there is decreased cell growth, viability, and a decrease in DHT/T ratios.[31] It has also shown the ability to reduce testosterone, androstenedione, and progesterone in androgen stimulated prostate cell lines by adenovirus vectors.[8]
Congenital deficiency of 5α-R3 at the gene SRD53A has been linked to a rare, autosomal recessive condition in which patients are born with severe intellectual dysfunction and cerebellar and ocular defects. The presumed deficiency is reduction of the terminal bond of polyprenol to dolichol, an important step in N-glycosylation of proteins, which in turn is important for proper folding of asparagine residues on nascent protein in the endoplasmic reticulum.[32]
Nervous system
Affective disorders
Isolation rearing has been shown to lower protein expression of 5α-reductase isoenzymes 1 and 2 in cortical and subcortical brain regions of rat models. However, the amount of 5α-reduced metabolite remained unaffected. This means isolation rearing likely leads to changes in the expression and activity of 5α-reductase in the brain, leading to dysregulation of dopamine neurotransmission, resulting in early chronic stress[33] Treatment with finasteride, a 5α-reductase inhibitor, has been shown to mimic the effects of SSRI's causing sexual dysfunction.[34] Research has shown that 5α-reductase is the rate-limiting enzyme in neurosteroid synthesis, specifically in the conversion of progesterone to allopregnanolone,[35] low levels of allopregnanolone has been tied to depression, anxiety and schizophrenia. Sleep deprivation can enhance 5α-reductase expression and activity in the prefrontal cortex, leading to mania-related symptoms in rats.[35] It is also contested whether the use of 5α-reductase inhibitors is associated with suicidal ideation and depression in patient populations who use them for benign prostatic hyperplasia.[36][37] These symptoms have been found during active use of inhibitors and in immediate followup.[36] However, it is unknown if these symptoms arise naturally from benign prostatic hyperplasia.[37]
Hypothalamic–pituitary–adrenal axis dysfunction
An alternative mechanism of cortisol regulation is regulated via 5α-reductase which catalyzes an A-ring reduction of cortisol, metabolizing the compound.[38] Type 1 and 2 of 5α-reductase are the principal enzymes involved in cortisol clearance through the liver.[39] Excess cortisol has been tied to non-alcoholic fatty liver disease (NAFLD), but in-vitro studies have found that an over expression of 5α-reductase type 2 can suppress lipogenesis.[40] The key role of 5α-reductase in cortisol breakdown and fat buildup has elucidated some of the side effects of 5α-reductase inhibitors. In randomized studies on human volunteers it was found that 5α-reductase inhibition through the use of dutasteride and finasteride can lead to hepatic lipid accumulation in men.[41] In critical illness, overstimulation of cortisol as part of a stress response can lead to decreased clearance of cortisol through the liver via 5α-reductase and kidneys via 11β-hydroxysteroid dehydrogenase type 2,[39] longterm elevation of cortisol can lead to Cushing's syndrome.
Nomenclature
This enzyme belongs to the family of oxidoreductases, to be specific, those acting on the CH-CH group of donor with other acceptors. The systematic name of this enzyme class is 3-oxo-5α-steroid:acceptor Δ4-oxidoreductase. Other names in common use include:
^Pinna G, Agis-Balboa RC, Pibiri F, Nelson M, Guidotti A, Costa E (October 2008). "Neurosteroid biosynthesis regulates sexually dimorphic fear and aggressive behavior in mice". Neurochemical Research. 33 (10): 1990–2007. doi:10.1007/s11064-008-9718-5. PMID18473173. S2CID19338424.
^ abcdYamana K, Labrie F, Luu-The V (August 2010). "Human type 3 5α-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride". Hormone Molecular Biology and Clinical Investigation. 2 (3): 293–9. doi:10.1515/hmbci.2010.035. PMID25961201. S2CID28841145.
^ abPaba S, Frau R, Godar SC, Devoto P, Marrosu F, Bortolato M (2011). "Steroid 5α-reductase as a novel therapeutic target for schizophrenia and other neuropsychiatric disorders". Current Pharmaceutical Design. 17 (2): 151–67. doi:10.2174/138161211795049589 (inactive 1 November 2024). PMID21361868.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
^Weinstein BI, Kandalaft N, Ritch R, Camras CB, Morris DJ, Latif SA, et al. (June 1991). "5 alpha-dihydrocortisol in human aqueous humor and metabolism of cortisol by human lenses in vitro". Investigative Ophthalmology & Visual Science. 32 (7): 2130–5. PMID2055703.
^Kenyon CJ, Brem AS, McDermott MJ, Deconti GA, Latif SA, Morris DJ (May 1983). "Antinatriuretic and kaliuretic activities of the reduced derivatives of aldosterone". Endocrinology. 112 (5): 1852–6. doi:10.1210/endo-112-5-1852. PMID6403339.
^Ahmed S, Denison S (September 1998). "Mechanism based representation of the active site of 5 alpha-reductase (5AR)". Bioorganic & Medicinal Chemistry Letters. 8 (18): 2615–70. doi:10.1016/S0960-894X(98)00463-6. PMID9873591.
^Andersson S (2001). "Steroidogenic enzymes in skin". European Journal of Dermatology. 11 (4): 293–5. PMID11399532.
^Irwig MS, Kolukula S (June 2011). "Persistent sexual side effects of finasteride for male pattern hair loss". The Journal of Sexual Medicine. 8 (6): 1747–53. doi:10.1111/j.1743-6109.2011.02255.x. PMID21418145.
^Tian G, Stuart JD, Moss ML, Domanico PL, Bramson HN, Patel IR, et al. (March 1994). "17 beta-(N-tert-butylcarbamoyl)-4-aza-5 alpha-androstan-1-en-3-one is an active site-directed slow time-dependent inhibitor of human steroid 5 alpha-reductase 1". Biochemistry. 33 (8): 2291–6. doi:10.1021/bi00174a041. PMID8117686.
^McConnell JD, Wilson JD, George FW, Geller J, Pappas F, Stoner E (March 1992). "Finasteride, an inhibitor of 5 alpha-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia". The Journal of Clinical Endocrinology and Metabolism. 74 (3): 505–8. doi:10.1210/jcem.74.3.1371291. PMID1371291.
^Andriole GL, Humphrey P, Ray P, Gleave ME, Trachtenberg J, Thomas LN, et al. (September 2004). "Effect of the dual 5alpha-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer". The Journal of Urology. 172 (3): 915–9. doi:10.1097/01.ju.0000136430.37245.b9. PMID15310997.
^Moss GP (December 1989). "IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989". European Journal of Biochemistry. 186 (3): 429–58. doi:10.1111/j.1432-1033.1989.tb15228.x. PMID2606099.
^Bortolato M, Devoto P, Roncada P, Frau R, Flore G, Saba P, et al. (June 2011). "Isolation rearing-induced reduction of brain 5α-reductase expression: relevance to dopaminergic impairments". Neuropharmacology. 60 (7–8): 1301–8. doi:10.1016/j.neuropharm.2011.01.013. PMID21256141. S2CID20164197.
^Giatti S, Diviccaro S, Panzica G, Melcangi RC (August 2018). "Post-finasteride syndrome and post-SSRI sexual dysfunction: two sides of the same coin?". Endocrine. 61 (2): 180–193. doi:10.1007/s12020-018-1593-5. PMID29675596. S2CID4974636.
Hasapi dengan satu senar. Hasapi adalah salah satu alat musik tradisional Batak Toba yang dikelompokkan ke dalam alat musik dawai atau senar, dalam bahasa Indonesia sering disebut Kecapi Batak.[1] Jenis-jenis Hasapi Hasapi terdiri dari: Hasapi ende (pluked lute dua senar) adalah instrumen pembawa melodi dan merupakan instrumen yang dianggap paling utama dalam ensambel gondang hasapi. Hasapi doal (pluked flude dua senar), instrumen ini sama dengan hasapi ende namun dalam permainannya h...
Wayang kulit dilihat pada sisi bayangannya. Batik Budaya Jawa adalah budaya yang berasal dari masyarakat pulau Jawa dan dianut oleh masyarakat Jawa khususnya di Banten Utara, Jawa Barat Utara, Jawa Tengah, Yogyakarta, dan Jawa Timur. Budaya Jawa secara garis besar dapat dibagi menjadi 3 yaitu budaya Jawa Kulonan (Banten Utara-Jawa Barat Utara-Jawa Tengah Barat), budaya Jawa Tengah(Timur)-DIY, dan budaya Jawa Timur. Budaya Jawa mengutamakan keseimbangan, keselarasan dan keserasian dalam kehidu...
Artikel ini perlu diwikifikasi agar memenuhi standar kualitas Wikipedia. Anda dapat memberikan bantuan berupa penambahan pranala dalam, atau dengan merapikan tata letak dari artikel ini. Untuk keterangan lebih lanjut, klik [tampil] di bagian kanan. Mengganti markah HTML dengan markah wiki bila dimungkinkan. Tambahkan pranala wiki. Bila dirasa perlu, buatlah pautan ke artikel wiki lainnya dengan cara menambahkan [[ dan ]] pada kata yang bersangkutan (lihat WP:LINK untuk keterangan lebih lanjut...
Dusan Djurić Informasi pribadiNama lengkap Dusan Predrag Djurić[1]Tanggal lahir 13 September 1984 (umur 39)Tempat lahir Halmstad, SwediaTinggi 1,81 m (5 ft 11+1⁄2 in)Posisi bermain GelandangInformasi klubKlub saat ini ValenciennesNomor 7Karier junior HalmstadKarier senior*Tahun Tim Tampil (Gol)2003–2007 Halmstad 116 (16)2008–2012 Zürich 118 (28)2012– Valenciennes 4 (0)Tim nasional‡2004–2006 Swedia U-21 21 (2)2005–2010 Swedia 8 (0) * Penampilan...
Greg Grunberg Gregory Phillip Greg Grunberg (lahir 11 Juli 1966) merupakan seorang aktor berkebangsaan Amerika Serikat. Dia pernah bermain di film utamanya seperti Sean Blumberg di Felicity (1998–2002) dan Eric Weiss di Alias (2001–2006). Dia dilahirkan di Los Angeles, California. Dia berkarier di dunia film sejak tahun 1996. Filmografi Tahun Judul Sebagai Catatan 1996 The Pallbearer Bobby (uncredited) film 1998 BASEketball Wilke film 1998 Diagnosis Murder Brad Carver Seri TV 1998–2002 ...
United States historic placeHarriman City HallU.S. National Register of Historic Places Postcard depicting Temperance HallShow map of TennesseeShow map of the United StatesLocationRoane and Walden Sts., Harriman, TennesseeCoordinates35°56′02″N 84°33′06″W / 35.9340°N 84.5516°W / 35.9340; -84.5516Area1 acre (0.40 ha)Built1890Built byEast Tennessee Land Co.NRHP reference No.71000828[1]Added to NRHPApril 16, 1971 American Temperance Unive...
The topic of this article may not meet Wikipedia's notability guideline for music. Please help to demonstrate the notability of the topic by citing reliable secondary sources that are independent of the topic and provide significant coverage of it beyond a mere trivial mention. If notability cannot be shown, the article is likely to be merged, redirected, or deleted.Find sources: Hunter & Prey – news · newspapers · books · scholar · JSTOR (May 2016...
1992 Portuguese Grand Prix Race 14 of 16 in the 1992 Formula One World Championship Race detailsDate 27 September 1992Official name XXI Grande Premio SG Gigante de PortugalLocation Autódromo do Estoril, Estoril, PortugalCourse Permanent racing facilityCourse length 4.349 km (2.703 miles)Distance 71 laps, 308.779 km (191.913 miles)Weather Dry, sunny, windyPole positionDriver Nigel Mansell Williams-RenaultTime 1:13.041Fastest lapDriver Ayrton Senna McLaren-HondaTime 1:16.272 on lap 66PodiumFir...
У этого термина существуют и другие значения, см. Западный округ. Западный внутригородской округ город Краснодар Дата основания 1936 год Дата упразднения 1994 Прежние имена Кагановичский, Ленинский районы Микрорайоны Дубинка, Черёмушки, Покровка Площадь 22[1] км² Насе...
This article is about the church located in Yerevan, Armenia. For the church of the same name located just outside Zoravan, see Gharghavank. For the church of the same name located in Jebrail, see Jebrail. Zoravor Surp Astvatsatsin Church Զորավոր Սուրբ Աստվածածին եկեղեցիZoravor Surp Astvatsatsin ChurchReligionAffiliationArmenian Apostolic ChurchDistrictKentron DistrictRegionYerevanEcclesiastical or organizational statusChurchStatusActiveLocationLocationin a courty...
Agostino Burgarella Ajola (Favignana, 4 novembre 1823 – Suez, 28 novembre 1892) è stato un imprenditore e patriota italiano. Biografia Cappella di Agostino Burgarella Ajola nel cimitero di Trapani Agostino Burgarella Ajola nacque a Favignana il 4 novembre 1823, da Agostino Burgarella e Aurelia Ajola[1]. Agostino Burgarella Ajola fu un industriale, banchiere e maggiore dell'esercito meridionale. Partecipò attivamente alla spedizione dei Mille del 1860[2][3]. Nel giu...
Державний комітет телебачення і радіомовлення України (Держкомтелерадіо) Приміщення комітетуЗагальна інформаціяКраїна УкраїнаДата створення 2003Керівне відомство Кабінет Міністрів УкраїниРічний бюджет 1 964 898 500 ₴[1]Голова Олег НаливайкоПідвідомчі ор...
烏克蘭總理Прем'єр-міністр України烏克蘭國徽現任杰尼斯·什米加尔自2020年3月4日任命者烏克蘭總統任期總統任命首任維托爾德·福金设立1991年11月后继职位無网站www.kmu.gov.ua/control/en/(英文) 乌克兰 乌克兰政府与政治系列条目 宪法 政府 总统 弗拉基米尔·泽连斯基 總統辦公室 国家安全与国防事务委员会 总统代表(英语:Representatives of the President of Ukraine) 总...
Unjuk rasa Pakistan 2023pendukung Imran Khan dan Imran Khan di IslamabadTanggal17 mei 2023-sekarangSebab Penangkapan Imran Khan dengan dugaan korupsi Percobaan pembunuhan Imran Khan Kabar aparat keamanan menembak demonstran Pihak terlibat pendukung Imran KhanPartai Pakistan Tehreek-e-Insaf Pemerintah PakistanTokoh utama Kepemimpinan tidak terpusat Shehbaz SharifJumlah korbanKorban jiwa3 polisi Para wanita pendukung Imran Khan Unjuk rasa Pakistan 2023 terjadi karna pada selasa 16 mei, 2023 Pih...
مطار الكويت الدولي إياتا: KWI – ايكاو: OKBK موجز نوع المطار عام/عسكري. المشغل الإدارة العامة للطيران المدني. يخدم دولة الكويت. البلد الكويت الموقع محافظة الفروانية - الكويت. الارتفاع 63 م؛ 206 قدم إحداثيات 29°13′36″N 47°58′48″E / 29.226777777778°N 47.979972222222°E / 29.226777777778; 47.979972...
American basketball player (born 1992) Joe YoungYoung with the Indiana Pacers in 2018No. 3 – Fujian SturgeonsPositionPoint guard / shooting guardLeagueCBAPersonal informationBorn (1992-06-27) June 27, 1992 (age 31)Houston, Texas, U.S.Listed height6 ft 2 in (1.88 m)Listed weight185 lb (84 kg)Career informationHigh schoolYates (Houston, Texas)College Houston (2011–2013) Oregon (2013–2015) NBA draft2015: 2nd round, 43rd overall pickSelected by the Indi...
This article includes a list of references, related reading, or external links, but its sources remain unclear because it lacks inline citations. Please help improve this article by introducing more precise citations. (November 2017) (Learn how and when to remove this message) Historia Polonica, Vincenti Kadłubkonis Episcopi Cracoviensis, 1612 Chronica seu originale regum et principum Poloniae, short name Chronica Polonorum, is a Latin history of Poland written by Wincenty Kadłubek between ...