37639-46-6Relevant articles and documents
Novel insights into oxidation of fatty acids and fatty alcohols by cytochrome P450 monooxygenase CYP4B1
Thesseling, Florian A.,Hutter, Michael C.,Wiek, Constanze,Kowalski, John P.,Rettie, Allan E.,Girhard, Marco
, (2019/12/12)
CYP4B1 is an enigmatic mammalian cytochrome P450 monooxygenase acting at the interface between xenobiotic and endobiotic metabolism. A prominent CYP4B1 substrate is the furan pro-toxin 4-ipomeanol (IPO). Our recent investigation on metabolism of IPO related compounds that maintain the furan functionality of IPO while replacing its alcohol group with alkyl chains of varying structure and length revealed that, in addition to cytotoxic reactive metabolite formation (resulting from furan activation) non-cytotoxic ω-hydroxylation at the alkyl chain can also occur. We hypothesized that substrate reorientations may happen in the active site of CYP4B1. These findings prompted us to re-investigate oxidation of unsaturated fatty acids and fatty alcohols with C9–C16 carbon chain length by CYP4B1. Strikingly, we found that besides the previously reported ω- and ω-1-hydroxylations, CYP4B1 is also capable of α-, β-, γ-, and δ-fatty acid hydroxylation. In contrast, fatty alcohols of the same chain length are exclusively hydroxylated at ω, ω-1, and ω-2 positions. Docking results for the corresponding CYP4B1-substrate complexes revealed that fatty acids can adopt U-shaped bonding conformations, such that carbon atoms in both arms may approach the heme-iron. Quantum chemical estimates of activation energies of the hydrogen radical abstraction by the reactive compound 1 as well as electron densities of the substrate orbitals led to the conclusion that fatty acid and fatty alcohol oxidations by CYP4B1 are kinetically controlled reactions.
Light-Driven Kinetic Resolution of α-Functionalized Carboxylic Acids Enabled by an Engineered Fatty Acid Photodecarboxylase
Xu, Jian,Hu, Yujing,Fan, Jiajie,Arkin, Mamatjan,Li, Danyang,Peng, Yongzhen,Xu, Weihua,Lin, Xianfu,Wu, Qi
supporting information, p. 8474 - 8478 (2019/05/24)
Chiral α-functionalized carboxylic acids are valuable precursors for a variety of medicines and natural products. Herein, we described an engineered fatty acid photodecarboxylase (CvFAP)-catalyzed kinetic resolution of α-amino acids and α-hydroxy acids, which provides the unreacted R-configured substrates with high yields and excellent stereoselectivity (ee up to 99 %). This efficient light-driven process requires neither NADPH recycling nor prior preparation of esters, which were required in previous biocatalytic approaches. The structure-guided engineering strategy is based on the scanning of large amino acids at hotspots to narrow the substrate binding tunnel. To the best of our knowledge, this is the first example of asymmetric catalysis by an engineered CvFAP.
Preparative Asymmetric Synthesis of Canonical and Non-canonical α-amino Acids Through Formal Enantioselective Biocatalytic Amination of Carboxylic Acids
Dennig, Alexander,Blaschke, Fabio,Gandomkar, Somayyeh,Tassano, Erika,Nidetzky, Bernd
supporting information, (2019/02/09)
Chemical and biocatalytic synthesis of non-canonical α-amino acids (ncAAs) from renewable feedstocks and using mild reaction conditions has not efficiently been solved. Here, we show the development of a three-step, scalable and modular one-pot biocascade for linear conversion of renewable fatty acids (FAs) into enantiopure l-α-amino acids. In module 1, selective α-hydroxylation of FAs is catalyzed by the P450 peroxygenase P450CLA. By using an automated H2O2 supplementation system, efficient conversion (46 to >99%; TTN>3300) of a broad range of FAs (C6:0 to C16:0) into valuable α-hydroxy acids (α-HAs; >90% α-selective) is shown on preparative scale (up to 2.3 g L?1 isolated product). In module 2, a redox-neutral hydrogen borrowing cascade (alcohol dehydrogenase/amino acid dehydrogenase) allowed further conversion of α-HAs into l-α-AAs (20 to 99%). Enantiopure l-α-AAs (e.e. >99%) including the pharma synthon l-homo-phenylalanine can be obtained at product titers of up to 2.5 g L?1. Based on renewables and excellent atom economy, this biocascade is among the shortest and greenest synthetic routes to structurally diverse and industrially relevant ncAAs. (Figure presented.).
