Identification of Novel Metabolic Pathways of Pioglitazone in Hepatocytes: N-Glucuronidation of Thiazolidinedione Ring and Sequential Ring-Opening Pathway

2010 ◽  
Vol 38 (6) ◽  
pp. 946-956 ◽  
Author(s):  
Minoru Uchiyama ◽  
Thomas Fischer ◽  
Juergen Mueller ◽  
Minoru Oguchi ◽  
Naotoshi Yamamura ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Ring Opening

scholarly journals Structure of aryl O-demethylase offers molecular insight into a catalytic tyrosine-dependent mechanism

2017 ◽  
Vol 114 (16) ◽  
pp. E3205-E3214 ◽  
Author(s):  
Amanda C. Kohler ◽  
Matthew J. L. Mills ◽  
Paul D. Adams ◽  
Blake A. Simmons ◽  
Kenneth L. Sale
Keyword(s):  
Binding Site ◽  
Metabolic Pathways ◽  
Ring Opening ◽  
Geometry Optimization ◽  
Tca Cycle ◽  
Biofuel Production ◽  
Site Location ◽  
Insight Into ◽  
Dependent Mechanism

Some strains of soil and marine bacteria have evolved intricate metabolic pathways for using environmentally derived aromatics as a carbon source. Many of these metabolic pathways go through intermediates such as vanillate, 3-O-methylgallate, and syringate. Demethylation of these compounds is essential for downstream aryl modification, ring opening, and subsequent assimilation of these compounds into the tricarboxylic acid (TCA) cycle, and, correspondingly, there are a variety of associated aryl demethylase systems that vary in complexity. Intriguingly, only a basic understanding of the least complex system, the tetrahydrofolate-dependent aryl demethylase LigM from Sphingomonas paucimobilis, a bacterial strain that metabolizes lignin-derived aromatics, was previously available. LigM-catalyzed demethylation enables further modification and ring opening of the single-ring aromatics vanillate and 3-O-methylgallate, which are common byproducts of biofuel production. Here, we characterize aryl O-demethylation by LigM and report its 1.81-Å crystal structure, revealing a unique demethylase fold and a canonical folate-binding domain. Structural homology and geometry optimization calculations enabled the identification of LigM’s tetrahydrofolate-binding site and protein–folate interactions. Computationally guided mutagenesis and kinetic analyses allowed the identification of the enzyme’s aryl-binding site location and determination of its unique, catalytic tyrosine-dependent reaction mechanism. This work defines LigM as a distinct demethylase, both structurally and functionally, and provides insight into demethylation and its reaction requirements. These results afford the mechanistic details required for efficient utilization of LigM as a tool for aryl O-demethylation and as a component of synthetic biology efforts to valorize previously underused aromatic compounds.

scholarly journals Microbiological degradation of bile acids, further degradation of a cholic acid metabolite containing the hexahydroindane nucleus by Corynebacterium equi

1977 ◽  
Vol 162 (2) ◽  
pp. 387-397 ◽  
Author(s):  
S Hayakawa ◽  
T Fujiwara
Keyword(s):  
Cholic Acid ◽  
Propionic Acid ◽  
Metabolic Pathways ◽  
Ring Opening ◽  
Initial Step ◽  
Valeric Acid ◽  
Acid Metabolite ◽  
Partial Synthesis ◽  
Initial Oxidation ◽  
Dioic Acid

1. The further degradation of a cholic acid (I) metabolite, (4R)-4-[4alpha-(2-carboxyethyl)-3aalpha-hexahydro-7abeta-methyl-5-oxoindan-1beta-yl]valeric acid (IIa), by Corynebacterium equi was investigated. This organism effected ring-opening and gave (4R)-4-[2alpha-(2-carboxyethyl)-3beta-(3-carboxypropionyl)-2beta-methylcyclopent-1beta-yl]valeric acid (VI). The new metabolite was isolated as its trimethyl ester and identified by partical synthesis. It was not utilized by C. equi. 2. (4R)-4[4alpha-(2-Carboxyethyl)-3aalpha-decahydro-8abeta-methyl5-oxa-6-oxoazulen-1beta-yl]valeric acid (IVa), which is a hypothetical initial oxidation product in the above degradation, was not converted by C. equi into the expected metabolite (VI), but into 3 - [2beta - [(2S) - tetrahydro - 5 - oxofur - 2 - yl] - 1beta - methyl - 5 - oxocyclopent - 1alpha - yl]-propionic acid (VIII), the structure of which was established by partial synthesis. 3. Both the possible precursors of the metabolite (VI), an isomer of the epsilon-lactone (IVa), the gamma-lactone (XIa), and the open form of these lactones, the hydroxytricarboxylic acid (V), were also not utilized by C. equi. 4. Under some incubation conditions, C. equi also converted compound (IIa) and 3-(3aalpha-hexahydro-7abeta-methyl-1,5-dioxoindan-4alpha-yl)propionic acid (IIb) into 5-methyl-4-oxo-octane-1,8-dioic acid (III), (4R)-4-(2,3,4,6,6abeta,7,8,9,9aalpha,9bbeta-decahydro-6abeta-methyl-3-oxo-1H-cyclopenta[f]quinolin-7beta-yl)valeric acid (VII) and probably a monohydroxy derivative of compound (IIa) and compound (III), respectively. 5. The possibility that an initial step in the degradation of compound (IIa) by C. equi is oxygenation of the Baeyer-Villiger type, yielding compound (IVa), is discussed. Metabolic pathways of compound (IIa) to compounds (III), (VI), (VII) and (VIII) are also considered.

Amino-functional polyethers: versatile, stimuli-responsive polymers

2020 ◽  
Vol 11 (24) ◽  
pp. 3940-3950 ◽  
Author(s):  
Patrick Verkoyen ◽  
Holger Frey
Keyword(s):  
Ring Opening ◽  
Review Article ◽  
Stimuli Responsive ◽  
New Class ◽  
Stimuli Responsive Polymers ◽  
Responsive Polymers

Amino-functional polyethers have emerged as a new class of “smart”, i.e. pH- and thermoresponsive materials. This review article summarizes the synthesis and applications of these materials, obtained from ring-opening of suitable epoxide monomers.

Accelerating Metabolic Pathways Simulation using GPUs

2010 ◽  
Author(s):  
Sohan Lal ◽  
Kolin Paul ◽  
James Gomes
Keyword(s):  
Metabolic Pathways

Mapping metabolic pathways in chemical property space paves the way for new leishmanicidals

Planta Medica ◽  
2016 ◽  
Vol 81 (S 01) ◽  
pp. S1-S381
Author(s):  
E Vikeved ◽  
R Buonfiglio ◽  
T Kogej ◽  
A Backlund
Keyword(s):  
Chemical Property ◽  
Metabolic Pathways ◽  
Property Space ◽  
The Way

METABOLISM OF PREGNENOLONE-3-SULPHATE IN THE PERFUSED DOG LIVER

1965 ◽  
Vol 49 (3) ◽  
pp. 427-435 ◽  
Author(s):  
K. D. Voigt ◽  
J. Tamm ◽  
U. Volkwein ◽  
H. Schedewie
Keyword(s):  
Metabolic Pathways ◽  
Dog Liver ◽  
Steroid Conjugates

ABSTRACT Pregnenolone-sulphate (400 mg) was perfused through isolated dog livers. The following steroids were isolated in the perfusate: pregnenolone, progesterone, dehydroepiandrosterone, androst-5-ene-diol and the two steroid conjugates, i. e. pregnenolone-sulphate and dehydroepiandrosterone-sulphate. Two »free« steroids and one steroid conjugate could not be characterized. A tentative scheme for the metabolic pathways of pregnenolone-sulphate is presented.

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