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Katarzyna M Romek - One of the best experts on this subject based on the ideXlab platform.
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a retro biosynthetic approach to the prediction of biosynthetic pathways from position specific isotope analysis as shown for tramadol
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Katarzyna M Romek, Gerald S Remaud, Virginie Silvestre, Germain Sotoing Taiwe, Florine Lecerfschmidt, Ahcene Boumendjel, Michel De Waard, Richard J RobinsAbstract:Tramadol, previously only known as a synthetic analgesic, has now been found in the bark and wood of roots of the African medicinal tree Nauclea latifolia . At present, no direct evidence is available as to the biosynthetic pathway of its unusual skeleton. To provide guidance as to possible biosynthetic precursors, we have adopted a novel approach of retro-biosynthesis based on the position-specific distribution of isotopes in the Extracted Compound. Relatively recent developments in isotope ratio monitoring by 13 C NMR spectrometry make possible the measurement of the nonstatistical position-specific natural abundance distribution of 13 C (δ 13 C i ) within the molecule with better than 1‰ precision. Very substantial variation in the 13 C positional distribution is found: between δ 13 C i = −11 and −53‰. Distribution is not random and it is argued that the pattern observed can substantially be interpreted in relation to known causes of isotope fractionation in natural products. Thus, a plausible biosynthetic scheme based on sound biosynthetic principals of precursor–substrate relationships can be proposed. In addition, data obtained from the 18 O/ 16 O ratios in the oxygen atoms of the Compound add support to the deductions made from the carbon isotope analysis. This paper shows how the use of 13 C NMR at natural abundance can help with proposing a biosynthetic route to Compounds newly found in nature or those difficult to tackle by conventional means.
David W Graham - One of the best experts on this subject based on the ideXlab platform.
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purification and physical chemical properties of methanobactin a chalkophore from methylosinus trichosporium ob3b
Biochemistry, 2005Co-Authors: Nadezhda A Galeva, Michail A Alterman, Cynthia K Larive, David W GrahamAbstract:Methanobactin is an extracellular, copper-binding chromopeptide from the methane-oxidizing bacterium, Methylosinus trichosporium OB3b, believed to be involved in copper detoxification, sequestration, and uptake. Although small (1217.2 Da), methanobactin possesses a complex three-dimensional macrocyclic structure with several unusual moieties. The molecule binds one copper and has the N-2-isopropylester-(4-thionyl-5-hydroxyimidazolate)-Gly1-Ser2-Cys3-Tyr4-pyrrolidine-(4-hydroxy-5-thionylimidazolate)-Ser5-Cys6-Met7 sequence [Kim, H. J., et al. (2004) Science 305, 1612−1615]. We report methods for purifying methanobactin from M. trichosporium OB3b and present initial evidence of its physiological function. MALDI-TOF MS was used to systematically monitor samples for optimizing purification conditions, and for detecting and analyzing specific metal−methanobactin complexes. Purification was performed by first stabilizing the Extracted Compound with copper followed by separation using reversed-phase HPLC in neut...
Richard J Robins - One of the best experts on this subject based on the ideXlab platform.
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a retro biosynthetic approach to the prediction of biosynthetic pathways from position specific isotope analysis as shown for tramadol
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Katarzyna M Romek, Gerald S Remaud, Virginie Silvestre, Germain Sotoing Taiwe, Florine Lecerfschmidt, Ahcene Boumendjel, Michel De Waard, Richard J RobinsAbstract:Tramadol, previously only known as a synthetic analgesic, has now been found in the bark and wood of roots of the African medicinal tree Nauclea latifolia . At present, no direct evidence is available as to the biosynthetic pathway of its unusual skeleton. To provide guidance as to possible biosynthetic precursors, we have adopted a novel approach of retro-biosynthesis based on the position-specific distribution of isotopes in the Extracted Compound. Relatively recent developments in isotope ratio monitoring by 13 C NMR spectrometry make possible the measurement of the nonstatistical position-specific natural abundance distribution of 13 C (δ 13 C i ) within the molecule with better than 1‰ precision. Very substantial variation in the 13 C positional distribution is found: between δ 13 C i = −11 and −53‰. Distribution is not random and it is argued that the pattern observed can substantially be interpreted in relation to known causes of isotope fractionation in natural products. Thus, a plausible biosynthetic scheme based on sound biosynthetic principals of precursor–substrate relationships can be proposed. In addition, data obtained from the 18 O/ 16 O ratios in the oxygen atoms of the Compound add support to the deductions made from the carbon isotope analysis. This paper shows how the use of 13 C NMR at natural abundance can help with proposing a biosynthetic route to Compounds newly found in nature or those difficult to tackle by conventional means.
R A Branch - One of the best experts on this subject based on the ideXlab platform.
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mephenytoin disposition and serum bile acids as indices of hepatic function in chronic viral hepatitis
Clinical Pharmacology & Therapeutics, 1997Co-Authors: Patricia A Arns, Adrian M Dibisceglie, Adedayo Adedoyin, Grant R. Wilkinson, Jeanne G. Waggoner, Jay H Hoofnagle, R A BranchAbstract:Background and objectives The effect of chronic viral hepatitis on liver function may vary from none to hepatic failure. Changes in function are usually the result of impaired hepatocyte function or altered vascular flow and architecture. Conventional liver function tests usually cannot distinguish contributions from these mechanisms or indicate degree of hepatic metabolic dysfunction. An alternative approach is to measure the hepatic metabolism of a highly Extracted Compound whose oral clearance and systemic bioavailability are dependent on both hepatocyte function and degree of portosystemic shunt. Methods The stereoselective metabolism of racemic mephenytoin (100 mg oral dose) was investigated in 35 patients with chronic viral hepatitis and compared with 153 healthy subjects. The mephenytoin RS enantiomeric ratio and cumulative excretion of the 4′-hydroxymephenytoin metabolite in a 0- to 8-hour urine sample were used in addition to serum bile acid levels and pathologic examination of biopsy specimens to assess the severity of hepatic dysfunction and portosystemic shunting. Results The patients as a group excreted less 4′-hydroxymephenytoin and had a smaller RS enantiomeric ratio of mephenytoin. The two measures were discriminatory between the patient groups classified by either serum cholylglycine level or pathologic examination of biopsy specimens. Combination of the two measures of mephenytoin metabolism allowed the patients to be classified into three groups: normal hepatocyte function without portosystemic shunt, normal hepatocyte function with portosystemic shunt, and low hepatocyte function with or without portosystemic shunt. Conclusion This study has shown the potential usefulness of mephenytoin metabolism as a sensitive indicator of hepatic pathologic condition with an ability to discriminate between contributory alternative mechanisms. Clinical Pharmacology & Therapeutics (1997) 62, 527–537; doi:
Nadezhda A Galeva - One of the best experts on this subject based on the ideXlab platform.
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purification and physical chemical properties of methanobactin a chalkophore from methylosinus trichosporium ob3b
Biochemistry, 2005Co-Authors: Nadezhda A Galeva, Michail A Alterman, Cynthia K Larive, David W GrahamAbstract:Methanobactin is an extracellular, copper-binding chromopeptide from the methane-oxidizing bacterium, Methylosinus trichosporium OB3b, believed to be involved in copper detoxification, sequestration, and uptake. Although small (1217.2 Da), methanobactin possesses a complex three-dimensional macrocyclic structure with several unusual moieties. The molecule binds one copper and has the N-2-isopropylester-(4-thionyl-5-hydroxyimidazolate)-Gly1-Ser2-Cys3-Tyr4-pyrrolidine-(4-hydroxy-5-thionylimidazolate)-Ser5-Cys6-Met7 sequence [Kim, H. J., et al. (2004) Science 305, 1612−1615]. We report methods for purifying methanobactin from M. trichosporium OB3b and present initial evidence of its physiological function. MALDI-TOF MS was used to systematically monitor samples for optimizing purification conditions, and for detecting and analyzing specific metal−methanobactin complexes. Purification was performed by first stabilizing the Extracted Compound with copper followed by separation using reversed-phase HPLC in neut...
