PMID- 11320247
OWN - NLM
STAT- MEDLINE
DCOM- 20010521
LR  - 20230501
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 98
IP  - 9
DP  - 2001 Apr 24
TI  - Efficient pyrophosphorolysis by a hepatitis B virus polymerase may be a 
      primer-unblocking mechanism.
PG  - 4984-9
AB  - Effective antiviral agents are thought to inhibit hepatitis B virus (HBV) DNA 
      synthesis irreversibly by chain termination because reverse transcriptases (RT) 
      lack an exonucleolytic activity that can remove incorporated nucleotides. 
      However, since the parameters governing this inhibition are poorly defined, fully 
      delineating the catalytic mechanism of the HBV-RT promises to facilitate the 
      development of antiviral drugs for treating chronic HBV infection. To this end, 
      pyrophosphorolysis and pyrophosphate exchange, two nonhydrolytic RT activities 
      that result in the removal of newly incorporated nucleotides, were characterized 
      by using endogenous avian HBV replication complexes assembled in vivo. Although 
      these activities are presumed to be physiologically irrelevant for every 
      polymerase examined, the efficiency with which they are catalyzed by the avian 
      HBV-RT strongly suggests that it is the first known polymerase to catalyze these 
      reactions under replicative conditions. The ability to remove newly incorporated 
      nucleotides during replication has important biological and clinical 
      implications: these activities may serve a primer-unblocking function in vivo. 
      Analysis of pyrophosphorolysis on chain-terminated DNA revealed that the potent 
      anti-HBV drug beta-l-(-)-2',3'-dideoxy-3'-thiacytidine (3TC) was difficult to 
      remove by pyrophosphorolysis, in contrast to ineffective chain terminators such 
      as ddC. This disparity may account for the strong antiviral efficacy of 3TC 
      versus that of ddC. The HBV-RT pyrophosphorolytic activity may therefore be a 
      novel determinant of antiviral drug efficacy, and could serve as a target for 
      future antiviral drug therapy. The strong inhibitory effect of cytoplasmic 
      pyrophosphate concentrations on viral DNA synthesis may also partly account for 
      the apparent slow rate of HBV genome replication.
FAU - Urban, S
AU  - Urban S
AD  - Department of Medical Microbiology and Immunology and Glaxo-Wellcome Heritage 
      Research Institute, University of Alberta, Edmonton, AB, Canada, T6G 2H7. 
      sin@mrc-lmb.cam.ac.uk
FAU - Urban, S
AU  - Urban S
FAU - Fischer, K P
AU  - Fischer KP
FAU - Tyrrell, D L
AU  - Tyrrell DL
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antiviral Agents)
RN  - 0 (DNA, Viral)
RN  - 0 (Diphosphates)
RN  - 0 (Reverse Transcriptase Inhibitors)
RN  - 2T8Q726O95 (Lamivudine)
RN  - 6L3XT8CB3I (Zalcitabine)
RN  - EC 2.7.7.49 (RNA-Directed DNA Polymerase)
SB  - IM
MH  - Animals
MH  - Antiviral Agents/pharmacology
MH  - Catalysis/drug effects
MH  - DNA Replication/drug effects
MH  - DNA, Viral/biosynthesis
MH  - Diphosphates/*metabolism/pharmacology
MH  - Ducks/*virology
MH  - Genome, Viral
MH  - Hepatitis B Virus, Duck/drug effects/*enzymology/genetics
MH  - Hydrolysis/drug effects
MH  - Kinetics
MH  - Lamivudine/pharmacology
MH  - Liver/virology
MH  - RNA-Directed DNA Polymerase/*metabolism
MH  - Reverse Transcriptase Inhibitors/pharmacology
MH  - Virion/drug effects/enzymology/genetics
MH  - Zalcitabine/pharmacology
PMC - PMC33150
EDAT- 2001/04/26 10:00
MHDA- 2001/05/25 10:01
PMCR- 2001/10/24
CRDT- 2001/04/26 10:00
PHST- 2001/04/26 10:00 [pubmed]
PHST- 2001/05/25 10:01 [medline]
PHST- 2001/04/26 10:00 [entrez]
PHST- 2001/10/24 00:00 [pmc-release]
AID - 98/9/4984 [pii]
AID - 091324398 [pii]
AID - 3243 [pii]
AID - 10.1073/pnas.091324398 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):4984-9. doi: 10.1073/pnas.091324398.