Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2'-Deoxyadenosine 3'-tetraphosphate (2'-deoxy-3'-A4P) and 2', 5'-dideoxyadenosine 3'-tetraphosphate (2',5'-dideoxy-3'-A4P) were synthesized, and their effects were tested on crude and purified forms of native adenylyl cyclases isolated from brain. Syntheses combined the method of alkoxide activation with the use of tribromoethyl phosphoromorpholino-chloridate as an initial phosphorylating agent. Inhibition of adenylyl cyclase was rapid in onset. With 2'-d-3'-A4P or 2',5'-dd-3'-A4P inhibition of a purified native enzyme conformed to a linear noncompetitive behavior with respect to substrate, metal-5'ATP. Order of potency was 2', 5'-dideoxy- > 2'-deoxyadenosine and 3'-tetraphosphate > 3'-triphosphate. Both mechanism of inhibition and rank order of potency were consistent with inhibition via the 3'-nucleotide-(P)-site on adenylyl cyclase. Neither 2',5'-dd-3'-ATP nor 2',5'-dd-3'-A4P had any effect on the activities of other adenosine nucleotide binding proteins such as Ca2+/calmodulin-sensitive cyclic nucleotide phosphodiesterase, Na+/K+-ATPase, or cAMP-dependent protein kinase. With purified adenylyl cyclase from bovine brain 2',5'-dd-3'-A4P and 2'-d-3'-A4P gave, respectively, IC50 values of 9.3 and 15 nM and Ki values of 23 and 53 nM. These 3'-nucleotides are the most potent regulators described for adenylyl cyclases.
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PMID:Adenine nucleoside 3'-tetraphosphates are novel and potent inhibitors of adenylyl cyclases. 973 5

Nucleoside analog reverse transcriptase inhibitors (NRTIs) are known to directly inhibit mitochondrial complex I activity as well as various mitochondrial kinases. Recent observations that complex I activity and superoxide production are modulated through cAMP-dependent phosphorylation suggests a mechanism through which NRTIs may affect mitochondrial respiration via kinase-dependent protein phosphorylation. In the current study, we examine the potential for NRTIs to inhibit the cAMP-dependent phosphorylation of complex I and the associated NADH:CoQ oxidoreductase activities and rates of superoxide production using HepG2 cells. Phosphoprotein staining of immunocaptured complex I revealed that 3'-azido-3'-deoxythymidine (AZT; 10 and 50 microM), AZT monophosphate (150 microM), and 2',3'-dideoxycytidine (ddC; 1 microM) prevented the phosphorylation of the NDUFB11 subunit of complex I. This was associated with a decrease in complex I activity with AZT and AZT monophosphate only. In the presence of succinate, superoxide production was increased with 2',3'-dideoxyinosine (ddI; 10 microM) and ddC (1 microM). In the presence of succinate+cAMP, AZT showed an inverse dose-dependent effect on superoxide production. None of the NRTIs examined inhibit PKA activity suggesting that the observed effects are due to a direct interaction with complex I. These data demonstrate a direct effect of NRTIs on cAMP-dependent regulation of mitochondrial bioenergetics independent of DNA polymerase-gamma activity; in the case of AZT, these observations may provide a mechanism for the observed long-term toxicity with this drug.
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PMID:Adenosine 3',5'-cyclic monophosphate (cAMP)-dependent phosphoregulation of mitochondrial complex I is inhibited by nucleoside reverse transcriptase inhibitors. 1790