A novel route of ATP synthesis.
Incorporation of the adenine moiety of 2'-deoxyadenosine (dAdo) into ATP, consistently observed in human erythrocytes, is a phenomenon which cannot be explained by the operation of any known pathway. We reported previously that this effect was not observed in adenine phosphoribosyltransferase-deficient erythrocytes showing that adenine must be an obligatory intermediate. However, generation of adenine from dAdo was difficult to reconcile with the operation of any known process in human cells, and involvement of S-adenosylhomocysteine hydrolase (SAH-hydrolase) was postulated. The present studies with intact human erythrocytes demonstrate that nucleoside analogues which inhibit SAH-hydrolase caused substantial attenuation of adenine transfer from dAdo into ATP. It was confirmed that dAdo is not a substrate of 5'deoxy-5'methylthioadenosine (5'MT-adenosine) phosphorylase. Inhibition of the transfer of the adenine moiety of dAdo into ATP did not correlate with inhibition of 5'MT-adenosine phosphorylase by nucleoside analogues. This report provides further evidence that the pathway involving nucleoside (adenosine) analogue binding to SAH-hydrolase, release of base and subsequent phosphoribosylation can operate in intact cells. The metabolic significance of this process relates to the possible generation of free bases (adenine) in the human body, ATP synthesis and nucleoside drug interconversions.
Smolenski
R T
RT
Purine Research Laboratory, UMDS Guy's Hospital, London Bridge, London, U.K.
Fabianowska-Majewska
K
K
Montero
C
C
Duley
J A
JA
Fairbanks
L D
LD
Marlewski
M
M
Simmonds
H A
HA
D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D043383:Adenosylhomocysteinase; D003839:Deoxyadenosines / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D008954:Models, Biological; D009705:Nucleosides / Q000494:pharmacology; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors / Q000378:metabolism
D003839:Deoxyadenosines; D009705:Nucleosides; D000255:Adenosine Triphosphate; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D006867:Hydrolases; D043383:Adenosylhomocysteinase; C058118:2'-deoxyadenosine