Metabolic effects of a methylthioadenosine phosphorylase substrate analog on African trypanosomes

• Published in: Biochemical pharmacology Vol. 57; no. 1; pp. 89 - 96
• Main Authors: Bacchi, Cyrus J, Goldberg, Burt, Rattendi, Donna, Gorrell, Thomas E, Spiess, Arthur J, Sufrin, Janice R
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 1999; Elsevier Science
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacokinetics; Adenosine - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Biological Transport; Deoxyadenosines - pharmacokinetics; Deoxyadenosines - pharmacology; Medical sciences; Methionine - metabolism; methionine recycling; Models, Chemical; Molecular Structure; Pharmacology. Drug treatments; polyamine synthesis; Polyamines - metabolism; protein methylation; Purine-Nucleoside Phosphorylase - metabolism; Putrescine - metabolism; S-Adenosylmethionine - metabolism; Spermidine - metabolism; Structure-Activity Relationship; Substrate Specificity; Thionucleosides - pharmacokinetics; Thionucleosides - pharmacology; Trypanocidal Agents - pharmacokinetics; Trypanocidal Agents - pharmacology; Trypanosoma brucei brucei - drug effects; Trypanosoma brucei brucei - metabolism; Trypanosoma brucei rhodesiense - drug effects; Trypanosoma brucei rhodesiense - metabolism; methionine recycling; polyamine synthesis; protein methylation; S-adenosylmethionine metabolism; Kinetoplastida; Protozoa; Protozoal disease; Polyamine; Purine derivatives; Adenosylmethionine; Enzyme; Transferases; Glycosyltransferases; Methionine; Parasitosis; Metabolism; In vitro; Phosphorylase; Infection; Protein synthesis; Parasiticid; Hexosyltransferases; Mechanism of action; Methylation; Trypanosoma brucei; Trypanosomiasis
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(98)00290-1

The effects of 5′-deoxy-5′-(hydroxyethylthio)adenosine (HETA), a trypanocidal analog of 5′-deoxy-5′-(methylthio)adenosine (MTA), on polyamine synthesis and
S-adenosylmethionine (AdoMet) metabolism were examined in bloodstream forms of
Trypanosoma brucei brucei. HETA was cleaved by trypanosome MTA phosphorylase at the same rate as the natural substrate, MTA, in a phosphate-dependent reaction. Fluorine substitution at the 2-position of the purine ring increased activity by ∼50%, whereas substitution with an amino group reduced activity to about one-third of the control. HETA was accumulated by trypanosomes with internal concentrations of 100–250 μM and >800 μM after a 15-min incubation with 1 and 10 μM, respectively. Trypanosomes preincubated with HETA metabolized it at a rate of 21.9 nmol/hr/mg protein. Preincubation of cells with HETA at 1 or 10 μM inhibited spermidine synthesis from [
3H]ornithine by 22–37%, and increased the cytosolic levels of AdoMet by 2- to 5-fold and that of MTA by up to 8-fold.
S-Adenosylhomocysteine (AdoHcy) levels also increased 1.5- to 7-fold in treated cells, whereas decarboxylated AdoMet decreased 65%. Preincubation of trypanosomes with HETA for 4 hr also reduced the incorporation of [
35S]methionine in trichloroacetic acid-precipitable material by 50–60%, and reduced the methyl group incorporation into protein from [U-
14C]methionine by 65–70%. Thus, HETA interferes with a series of biochemical events involving the participation of AdoMet and methionine in polyamine synthesis, protein synthesis, and transmethylation reactions.