scholarly journals Xanthine, xanthosine and its nucleotides: solution structures of neutral and ionic forms, and relevance to substrate properties in various enzyme systems and metabolic pathways.

2004 ◽  
Vol 51 (2) ◽  
pp. 493-531 ◽  
Author(s):  
Ewa Kulikowska ◽  
Borys Kierdaszuk ◽  
David Shugar
Keyword(s):  
Metabolic Pathways ◽  
Equilibrium Mixture ◽  
Solution Structures ◽  
Enzyme Systems ◽  
Alkyl Derivatives ◽  
Substrate Properties ◽  
Nucleoside Hydrolases ◽  
Nucleoside Phosphorylases ◽  
Xanthine Nucleotide ◽  
Striking Contrast

The 6-oxopurine xanthine (Xan, neutral form 2,6-diketopurine) differs from the corresponding 6-oxopurines guanine (Gua) and hypoxanthine (Hyp) in that, at physiological pH, it consists of a approximately 1:1 equilibrium mixture of the neutral and monoanionic forms, the latter due to ionization of N(3)-H, in striking contrast to dissociation of the N(1)-H in both Gua and Hyp at higher pH. In xanthosine (Xao) and its nucleotides the xanthine ring is predominantly, or exclusively, a similar monoanion at physiological pH. The foregoing has, somewhat surprisingly, been widely overlooked in studies on the properties of these compounds in various enzyme systems and metabolic pathways, including, amongst others, xanthine oxidase, purine phosphoribosyltransferases, IMP dehydrogenases, purine nucleoside phosphorylases, nucleoside hydrolases, the enzymes involved in the biosynthesis of caffeine, the development of xanthine nucleotide-directed G proteins, the pharmacological properties of alkylxanthines. We here review the acid/base properties of xanthine, its nucleosides and nucleotides, their N-alkyl derivatives and other analogues, and their relevance to studies on the foregoing. Included also is a survey of the pH-dependent helical forms of polyxanthylic acid, poly(X), its ability to form helical complexes with a broad range of other synthetic homopolynucleotides, the base pairing properties of xanthine in synthetic oligonucleotides, and in damaged DNA, as well as enzymes involved in circumventing the existence of xanthine in natural DNA.

scholarly journals Enzymatic synthesis and phosphorolysis of 4(2)-thioxo- and 6(5)-azapyrimidine nucleosides by E. coli nucleoside phosphorylases

2016 ◽  
Vol 12 ◽  
pp. 2588-2601 ◽  
Author(s):  
Vladimir A Stepchenko ◽  
Anatoly I Miroshnikov ◽  
Frank Seela ◽  
Igor A Mikhailopulo
Keyword(s):  
Purine Nucleoside Phosphorylase ◽  
Reaction Conditions ◽  
E Coli ◽  
No Formation ◽  
Structural Peculiarities ◽  
Substrate Properties ◽  
Nucleoside Phosphorylases ◽  
Derivatives Of

The trans-2-deoxyribosylation of 4-thiouracil (4SUra) and 2-thiouracil (2SUra), as well as 6-azauracil, 6-azathymine and 6-aza-2-thiothymine was studied using dG and E. coli purine nucleoside phosphorylase (PNP) for the in situ generation of 2-deoxy-α-D-ribofuranose-1-phosphate (dRib-1P) followed by its coupling with the bases catalyzed by either E. coli thymidine (TP) or uridine (UP) phosphorylases. 4SUra revealed satisfactory substrate activity for UP and, unexpectedly, complete inertness for TP; no formation of 2’-deoxy-2-thiouridine (2SUd) was observed under analogous reaction conditions in the presence of UP and TP. On the contrary, 2SU, 2SUd, 4STd and 2STd are good substrates for both UP and TP; moreover, 2SU, 4STd and 2’-deoxy-5-azacytidine (Decitabine) are substrates for PNP and the phosphorolysis of the latter is reversible. Condensation of 2SUra and 5-azacytosine with dRib-1P (Ba salt) catalyzed by the accordant UP and PNP in Tris∙HCl buffer gave 2SUd and 2’-deoxy-5-azacytidine in 27% and 15% yields, respectively. 6-Azauracil and 6-azathymine showed good substrate properties for both TP and UP, whereas only TP recognizes 2-thio-6-azathymine as a substrate. 5-Phenyl and 5-tert-butyl derivatives of 6-azauracil and its 2-thioxo derivative were tested as substrates for UP and TP, and only 5-phenyl- and 5-tert-butyl-6-azauracils displayed very low substrate activity. The role of structural peculiarities and electronic properties in the substrate recognition by E. coli nucleoside phosphorylases is discussed.

Metabolic Studies of Environmental Effects

PEDIATRICS ◽  
1974 ◽  
Vol 53 (5) ◽  
pp. 824-825
Author(s):  
Albert Dorfman
Keyword(s):  
Developmental Biology ◽  
Animal Models ◽  
Molecular Biology ◽  
Metabolic Pathways ◽  
Theoretical Basis ◽  
Developmental Process ◽  
Toxic Substance ◽  
Enzyme Systems ◽  
General Lesson ◽  
Developmental Parameter

Perhaps some of the comments already made here about developing a theoretical basis for predictive purposes were in disagreement because opportunities vary greatly with the model under discussion. Certainly the general lesson of molecular biology and biochemistry in the last two decades has been surprisingly opposite to that of toxicology in that metabolic pathways are remarkably similar in range, not merely from mouse to man but even from bacteria to man. It is at times hard to accept the claim that animal models are not too useful for studying teratogenesis. Some principles that have been reviewed today are worth summarizing, because if one thinks of certain parameters, such as the final toxic substance (frequently a metabolite of the original pollutant) there is probably not much difference among various species or organisms. At least so it seems from study of enzyme systems. If one considers simpler situations, such as mercury pollution, he can realize the validity of this concept. THREE PARAMETERS OF TOXICITY One could possibly look at the situation as follows: at various stages of the developmental process, starting from the fertilized ovum and progressing to the mature organism or even the aged organism, there are enzymological differences which have become of interest in developmental biology. In particular, in pediatrics we know about programmed processes that go forward inevitably, and others which are subject to control by hormonal influences, by administration of certain substances, or by induction. In the interpretation of any kind of toxic effect, we must consider if our developmental parameter will or will not be toxic at certain stages of development, as I will ifiustrate later.

scholarly journals Identification of metabolic pathways and enzyme systems involved in the in vitro human hepatic metabolism of dronedarone, a potent new oral antiarrhythmic drug

2014 ◽  
Vol 2 (3) ◽  
Author(s):  
Sylvie Klieber ◽  
Catherine Arabeyre‐Fabre ◽  
Patricia Moliner ◽  
Eric Marti ◽  
Martine Mandray ◽  
...  
Keyword(s):  
Antiarrhythmic Drug ◽  
Metabolic Pathways ◽  
Hepatic Metabolism ◽  
Enzyme Systems

FORMATION OF UREA IN LIVER HOMOGENATES FROM CITRULLINE AND VARIOUS N-ALKYL DERIVATIVES OF ASPARTIG ACID

1963 ◽  
Vol 41 (1) ◽  
pp. 2297-2305 ◽  
Author(s):  
R. Charbonneau ◽  
L. Berlinguet
Keyword(s):  
Amino Acids ◽  
Carboxylic Acid ◽  
Aspartic Acid ◽  
Metabolic Pathways ◽  
Inhibitory Effect ◽  
Urea Synthesis ◽  
Alkyl Derivatives ◽  
Amino Acid Analogues ◽  
Liver Homogenates ◽  
Derivatives Of

The effects of various N-alkylated derivatives of aspartic acid on the synthesis of urea by rat liver homogenates have been studied. At 5 × 10−3 M concentration, N-methyl, N-ethyl, N-isopropyl, and N-cyclohexyl aspartic acids are not utilized and have no effect on the formation of urea. At this concentration, N-allyl-DL-aspartic acid inhibits the formation of endogenous urea by 77%. At concentrations of 2.5 to 7.5 × 10−2 M, N-methyl, N-ethyl, and N-isopropyl aspartic acids slightly increase the formation of endogenous urea; this is about 15% of the value obtained when aspartic acid alone is added at the same concentration. In the case of simple N-alkylated aspartic acids, liver homogenates are able to cleave the alkylated chain with the result that a small amount of urea synthesis is possible. N-allylaspartic acid totally inhibits the formation of urea from aspartic acid at a relatively low concentration of 6.2 × 10−3 M. N-cyclohexylaspartic acid has also an inhibitory effect which is ten times less pronounced than that of the N-allyl derivative.Natural amino acids such as DL- and L-valine, DL- and L-leucine, DL- and L-lysine, DL-alanine and glycine, at concentrations of 1.2 to 5 × 10−2 M, also inhibit the formation of urea. This inhibition is probably due to the fact that other metabolic pathways, used by these amino acids, have priority over the formation of urea. Amino acid analogues, such as 1-aminocyclopentane carboxylic acid and 1-amino-2-methylcyclopentane-carboxylic acid, do not have any effect on the synthesis of urea.A free amino group in the aspartic acid molecule seems to be essential for the synthesis of argininosuccinic acid.

FORMATION OF UREA IN LIVER HOMOGENATES FROM CITRULLINE AND VARIOUS N-ALKYL DERIVATIVES OF ASPARTIG ACID

1963 ◽  
Vol 41 (11) ◽  
pp. 2297-2305 ◽  
Author(s):  
R. Charbonneau ◽  
L. Berlinguet
Keyword(s):  
Amino Acids ◽  
Carboxylic Acid ◽  
Aspartic Acid ◽  
Metabolic Pathways ◽  
Inhibitory Effect ◽  
Urea Synthesis ◽  
Alkyl Derivatives ◽  
Amino Acid Analogues ◽  
Liver Homogenates ◽  
Derivatives Of

The effects of various N-alkylated derivatives of aspartic acid on the synthesis of urea by rat liver homogenates have been studied. At 5 × 10−3 M concentration, N-methyl, N-ethyl, N-isopropyl, and N-cyclohexyl aspartic acids are not utilized and have no effect on the formation of urea. At this concentration, N-allyl-DL-aspartic acid inhibits the formation of endogenous urea by 77%. At concentrations of 2.5 to 7.5 × 10−2 M, N-methyl, N-ethyl, and N-isopropyl aspartic acids slightly increase the formation of endogenous urea; this is about 15% of the value obtained when aspartic acid alone is added at the same concentration. In the case of simple N-alkylated aspartic acids, liver homogenates are able to cleave the alkylated chain with the result that a small amount of urea synthesis is possible. N-allylaspartic acid totally inhibits the formation of urea from aspartic acid at a relatively low concentration of 6.2 × 10−3 M. N-cyclohexylaspartic acid has also an inhibitory effect which is ten times less pronounced than that of the N-allyl derivative.Natural amino acids such as DL- and L-valine, DL- and L-leucine, DL- and L-lysine, DL-alanine and glycine, at concentrations of 1.2 to 5 × 10−2 M, also inhibit the formation of urea. This inhibition is probably due to the fact that other metabolic pathways, used by these amino acids, have priority over the formation of urea. Amino acid analogues, such as 1-aminocyclopentane carboxylic acid and 1-amino-2-methylcyclopentane-carboxylic acid, do not have any effect on the synthesis of urea.A free amino group in the aspartic acid molecule seems to be essential for the synthesis of argininosuccinic acid.

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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