3614-61-7Relevant academic research and scientific papers
A Dual Role Reductase from Phytosterols Catabolism Enables the Efficient Production of Valuable Steroid Precursors
Peng, Haidong,Wang, Yaya,Jiang, Kai,Chen, Xinru,Zhang, Wenlu,Zhang, Yanan,Deng, Zixin,Qu, Xudong
supporting information, p. 5414 - 5420 (2021/02/05)
4-Androstenedione (4-AD) and progesterone (PG) are two of the most important precursors for synthesis of steroid drugs, however their current manufacturing processes suffer from low efficiency and severe environmental issues. In this study, we decipher a dual-role reductase (mnOpccR) in the phytosterols catabolism, which engages in two different metabolic branches to produce the key intermediate 20-hydroxymethyl pregn-4-ene-3-one (4-HBC) through a 4-e reduction of 3-oxo-4-pregnene-20-carboxyl-CoA (3-OPC-CoA) and 2-e reduction of 3-oxo-4-pregnene-20-carboxyl aldehyde (3-OPA), respectively. Inactivation or overexpression of mnOpccR in the Mycobacterium neoaurum can achieve exclusive production of either 4-AD or 4-HBC from phytosterols. By utilizing a two-step synthesis, 4-HBC can be efficiently converted into PG in a scalable manner (100 gram scale). This study deciphers a pivotal biosynthetic mechanism of phytosterol catabolism and provides very efficient production routes of 4-AD and PG.
Activity of 3-ketosteroid 9α-hydroxylase (KshAB) indicates cholesterol side chain and ring degradation occur simultaneously in Mycobacterium tuberculosis
Capyk, Jenna K.,Casabon, Israel,Gruninger, Robert,Strynadka, Natalie C.,Eltis, Lindsay D.
experimental part, p. 40717 - 40724 (2012/06/29)
Mycobacterium tuberculosis (Mtb), a significant global pathogen, contains a cholesterol catabolic pathway. Although the precise role of cholesterol catabolism in Mtb remains unclear, the Rieske monooxygenase in this pathway, 3-ketosteroid 9α-hydroxylase (KshAB), has been identified as a virulence factor. To investigate the physiological substrate of KshAB, a rhodococcal acyl-CoA synthetase was used to produce the coenzyme A thioesters of two cholesterol derivatives: 3-oxo-23,24-bisnorchol-4- en-22-oic acid (forming 4-BNC-CoA) and 3-oxo-23,24-bisnorchola- 1,4-dien-22-oic acid (forming 1,4-BNC-CoA). The apparent specificity constant (kcat/Km) of KshAB for the CoA thioester substrates was 20-30 times that for the corresponding 17-keto compounds previously proposed as physiological substrates. The apparent KmO2 was 90 ± 10 μM in the presence of 1,4-BNC-CoA, consistent with the value for two other cholesterol catabolic oxygenases. The Δ1 ketosteroid dehydrogenase KstD acted with KshAB to cleave steroid ring B with a specific activity eight times greater for a CoA thioester than the corresponding ketone. Finally, modeling 1,4-BNC-CoA into the KshA crystal structure suggested that the CoA moiety binds in a pocket at the mouth of the active site channel and could contribute to substrate specificity. These results indicate that the physiological substrates of KshAB are CoA thioester intermediates of cholesterol side chain degradation and that side chain and ring degradation occur concurrently in Mtb. This finding has implications for steroid metabolites potentially released by the pathogen during infection and for the design of inhibitors for cholesterol-degrading enzymes. The methodologies and rhodococcal enzymes used to generate thioesters will facilitate the further study of cholesterol catabolism.
Isolation, biological significance, synthesis, and cytotoxic evaluation of new natural parathiosteroids A-C and analogues from the soft coral Paragorgia sp
Poza, Javier Jesus,Fernandez, Rogelio,Reyes, Fernando,Rodriguez, Jaime,Jimenez, Carlos
, p. 7978 - 7984 (2008/12/22)
(Chemical Equation Presented) Three unusual new steroid thioesters, parathiosteroids A-C (1a-3a), were isolated from the 2-propanol extract of the soft coral Paragorgia sp. collected in Madagascar. Their structures, determined by detailed spectroscopic analysis, were confirmed by synthesis and represent the first isolation of natural steroids bearing a C22 thioester in their side chain. These compounds displayed cytotoxicity against a panel of three human tumor cell lines at the micromolar level. The preparation of several analogues revealed structure/activity relationships in this type of steroids, for example, that the XCH2CH2NHCOCH3 moiety (X = S, O, NH) in the side chain is essential for the antiproliferative activity, and a low degree of oxidation in the A-ring results in higher bioactivity. These natural products could be biosynthetic intermediates in the steroid side chain degradation pathway involving activation with CoA and β-oxidations.
BIODEGRADATION OF CHOLESTEROL BY A MUTANT OF THE Mycobacterium SPECIES
Schwarz, Vladimir,Pihera, Pavel,Protiva, Jiri,Mickova, Ruzena
, p. 2713 - 2720 (2007/10/02)
The biodegradation of cholesterol by the Mycobacterium mutant CCM 3528 gave rise to 22-hydroxy-23,24-bisnorchola-1,4-diene-3-one (I) as the main product.The identified by-products were 24-norchola-1,4-diene-3,22-dione (IX), androsta-1,4-diene-3,17-dione (XV) and their unsaturated analogues, X and XVI respectively.
PROSTATIC CANCER. I. 6-METHYLENE-4-PREGNEN-3-ONES AS IRREVERSIBLE INHIBITORS OF RAT PROSTATIC Δ4-3-KETOSTEROID 5α-REDUCTASE
Petrow, Vladimir,Wang, Yueh-sha,Lack, Leon,Sandberg, Avery
, p. 121 - 140 (2007/10/02)
Some derivatives of 6-methylene-4-pregnen-3-one were studied as inhibitors of Δ4-3-ketosteroid 5α-reductase.Maximum inhibitory activity was shown by 17-acetoxy-6-methylene-4-pregnene-3,20-dione (AMPD).Irreversible inactivation was observed following preincubation of the enzyme with NADPH and AMPD.This inactivation was found to occur only in the presence of NADPH.As such enzyme inactivation was not due to the formation of a more inhibitory metabolic product, or to the formation of superoxide via a cytochrome P-450/NADPH pathway, it seemed likely that the observed inactivation was derived from an irreversible combination of the enzyme with AMPD.That this was probably the case was established by kinetic studies which revealed a pattern compatible with a kcat type of mechanism.
