Abacavir transport and metabolism (Homo sapiens)

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146, 9, 1211197, 18108, 131, 2, 17, 193194, 16cytosolendoplasmic reticulum membraneadenosinephosphotransferaseSLC22A2 NT5C2 tetramerHC-ABCG2 ADPcarbovirtriphosphateABCB1UDP-GlcAADAL abacavir5'-glucuronideADH1A PCK1Zn2+ Ade-RibAMPADPNAD+carbovir diphosphatecarbovirADPMg2+ NADHATPABCG2 dimercarbovirmonophosphateabacavirUDPSLC22A3 UDPGTSLC22A1 ADAL:ZnZn2+ H2OADH1A:2Zn2+ dimercyclopropylamineATPabacavirmonophosphateH2OabacavirATPIMPabacavir5'-carboxylic acidNT5C2 PiGUK1SLC22A1,2,3H+Ino101, 175, 158112


Description

Abacavir is a nucleoside analogue reverse transcriptase inhibitor with antiretroviral activity, widely used in combination with other drugs to treat HIV-1 infection (Yuen et al. 2008). Its uptake across the plasma membrane is mediated by organic cation transporters SLC22A1, 2, and 3; the transport proteins ABCB1 and ABCG2 mediate its efflux. Abacavir itself is a prodrug. Activation requires phosphorylation by a cytosolic adenosine phosphotransferase and deamination by ADAL deaminase to yield carbovir monophosphate. Cytosolic nucleotide kinases convert carbovir monophosphate to carbovir triphosphate, the active HIV reverse transcriptase inhibitor. Abacavir can be glucuronidated or oxidized to a 5'-carboxylate; these are the major forms in which it is excreted from the body. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 2161522
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: D'Eustachio, Peter

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Bibliography

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  1. Spychała J, Madrid-Marina V, Fox IH.; ''High Km soluble 5'-nucleotidase from human placenta. Properties and allosteric regulation by IMP and ATP.''; PubMed Europe PMC
  2. Johnson MA, Fridland A.; ''Phosphorylation of 2',3'-dideoxyinosine by cytosolic 5'-nucleotidase of human lymphoid cells.''; PubMed Europe PMC
  3. Shaik N, Giri N, Pan G, Elmquist WF.; ''P-glycoprotein-mediated active efflux of the anti-HIV1 nucleoside abacavir limits cellular accumulation and brain distribution.''; PubMed Europe PMC
  4. McDowell JA, Chittick GE, Ravitch JR, Polk RE, Kerkering TM, Stein DS.; ''Pharmacokinetics of [(14)C]abacavir, a human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, administered in a single oral dose to HIV-1-infected adults: a mass balance study.''; PubMed Europe PMC
  5. Yin SJ, Bosron WF, Magnes LJ, Li TK.; ''Human liver alcohol dehydrogenase: purification and kinetic characterization of the beta 2 beta 2, beta 2 beta 1, alpha beta 2, and beta 2 gamma 1 "Oriental" isoenzymes.''; PubMed Europe PMC
  6. Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, Ross DD.; ''A multidrug resistance transporter from human MCF-7 breast cancer cells.''; PubMed Europe PMC
  7. Minuesa G, Volk C, Molina-Arcas M, Gorboulev V, Erkizia I, Arndt P, Clotet B, Pastor-Anglada M, Koepsell H, Martinez-Picado J.; ''Transport of lamivudine [(-)-beta-L-2',3'-dideoxy-3'-thiacytidine] and high-affinity interaction of nucleoside reverse transcriptase inhibitors with human organic cation transporters 1, 2, and 3.''; PubMed Europe PMC
  8. Garvey EP, Krenitsky TA.; ''A novel human phosphotransferase highly specific for adenosine.''; PubMed Europe PMC
  9. Pan G, Giri N, Elmquist WF.; ''Abcg2/Bcrp1 mediates the polarized transport of antiretroviral nucleosides abacavir and zidovudine.''; PubMed Europe PMC
  10. Murakami E, Bao H, Mosley RT, Du J, Sofia MJ, Furman PA.; ''Adenosine deaminase-like protein 1 (ADAL1): characterization and substrate specificity in the hydrolysis of N(6)- or O(6)-substituted purine or 2-aminopurine nucleoside monophosphates.''; PubMed Europe PMC
  11. Walsh JS, Reese MJ, Thurmond LM.; ''The metabolic activation of abacavir by human liver cytosol and expressed human alcohol dehydrogenase isozymes.''; PubMed Europe PMC
  12. Wakabayashi K, Nakagawa H, Tamura A, Koshiba S, Hoshijima K, Komada M, Ishikawa T.; ''Intramolecular disulfide bond is a critical check point determining degradative fates of ATP-binding cassette (ABC) transporter ABCG2 protein.''; PubMed Europe PMC
  13. Faletto MB, Miller WH, Garvey EP, St Clair MH, Daluge SM, Good SS.; ''Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89.''; PubMed Europe PMC
  14. Yuen GJ, Weller S, Pakes GE.; ''A review of the pharmacokinetics of abacavir.''; PubMed Europe PMC
  15. Lange LG, Sytkowski AJ, Vallee BL.; ''Human liver alcohol dehydrogenase: purification, composition, and catalytic features.''; PubMed Europe PMC
  16. Ravitch JR, Moseley CG.; ''High-performance liquid chromatographic assay for abacavir and its two major metabolites in human urine and cerebrospinal fluid.''; PubMed Europe PMC
  17. Walldén K, Stenmark P, Nyman T, Flodin S, Gräslund S, Loppnau P, Bianchi V, Nordlund P.; ''Crystal structure of human cytosolic 5'-nucleotidase II: insights into allosteric regulation and substrate recognition.''; PubMed Europe PMC
  18. Klaassen CD, Aleksunes LM.; ''Xenobiotic, bile acid, and cholesterol transporters: function and regulation.''; PubMed Europe PMC
  19. Miller WH, Daluge SM, Garvey EP, Hopkins S, Reardon JE, Boyd FL, Miller RL.; ''Phosphorylation of carbovir enantiomers by cellular enzymes determines the stereoselectivity of antiviral activity.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101443view11:31, 1 November 2018ReactomeTeamreactome version 66
100981view21:09, 31 October 2018ReactomeTeamreactome version 65
100517view19:43, 31 October 2018ReactomeTeamreactome version 64
100063view16:27, 31 October 2018ReactomeTeamreactome version 63
99615view15:00, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93965view13:48, 16 August 2017ReactomeTeamreactome version 61
93563view11:27, 9 August 2017ReactomeTeamreactome version 61
92310view06:19, 20 May 2017EgonwOntology Term : 'xenobiotic metabolic pathway' added !
87032view14:51, 15 July 2016MkutmonOntology Term : 'abacavir drug pathway' added !
86664view09:23, 11 July 2016ReactomeTeamreactome version 56
83598view13:39, 27 November 2015Anweshaimproved layout
83313view10:45, 18 November 2015ReactomeTeamVersion54
81340view12:50, 21 August 2015ReactomeTeamVersion53
78029view14:19, 13 November 2014AnweshaImproved Layout
76926view08:19, 17 July 2014ReactomeTeamFixed remaining interactions
76631view12:00, 16 July 2014ReactomeTeamFixed remaining interactions
76515view11:41, 16 July 2014ReactomeTeamFixed remaining interactions
75962view10:02, 11 June 2014ReactomeTeamRe-fixing comment source
75664view10:56, 10 June 2014ReactomeTeamReactome 48 Update
75019view13:53, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74663view08:43, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ABCB1ProteinP08183 (Uniprot-TrEMBL)
ABCG2 dimerComplexR-HSA-917863 (Reactome)
ADAL ProteinQ6DHV7 (Uniprot-TrEMBL)
ADAL:ZnComplexR-HSA-2161178 (Reactome)
ADH1A ProteinP07327 (Uniprot-TrEMBL)
ADH1A:2Zn2+ dimerComplexR-HSA-71693 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
AMPMetaboliteCHEBI:16027 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ade-RibMetaboliteCHEBI:16335 (ChEBI)
GUK1ProteinQ16774 (Uniprot-TrEMBL)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HC-ABCG2 ProteinQ9UNQ0 (Uniprot-TrEMBL)
IMPMetaboliteCHEBI:17202 (ChEBI)
InoMetaboliteCHEBI:17596 (ChEBI)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
NT5C2 ProteinP49902 (Uniprot-TrEMBL)
NT5C2 tetramerComplexR-HSA-109318 (Reactome)
PCK1ProteinP35558 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
SLC22A1 ProteinO15245 (Uniprot-TrEMBL)
SLC22A1,2,3ComplexR-HSA-2161529 (Reactome)
SLC22A2 ProteinO15244 (Uniprot-TrEMBL)
SLC22A3 ProteinO75751 (Uniprot-TrEMBL)
UDP-GlcAMetaboliteCHEBI:17200 (ChEBI)
UDPMetaboliteCHEBI:17659 (ChEBI)
UDPGTR-HSA-2162090 (Reactome)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
abacavir 5'-carboxylic acidMetaboliteCHEBI:64192 (ChEBI)
abacavir 5'-glucuronideMetaboliteCHEBI:64189 (ChEBI)
abacavir monophosphateMetaboliteCHEBI:64112 (ChEBI)
abacavirMetaboliteCHEBI:421707 (ChEBI)
adenosine phosphotransferaseR-HSA-2161183 (Reactome)
carbovir monophosphateMetaboliteCHEBI:64116 (ChEBI)
carbovir triphosphateMetaboliteCHEBI:64174 (ChEBI)
carbovir diphosphateMetaboliteCHEBI:64172 (ChEBI)
carbovirMetaboliteCHEBI:421843 (ChEBI)
cyclopropylamineMetaboliteCHEBI:34660 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ABCB1mim-catalysisR-HSA-2161538 (Reactome)
ABCG2 dimermim-catalysisR-HSA-2161506 (Reactome)
ADAL:Znmim-catalysisR-HSA-2161195 (Reactome)
ADH1A:2Zn2+ dimermim-catalysisR-HSA-2162078 (Reactome)
ADPArrowR-HSA-2161506 (Reactome)
ADPArrowR-HSA-2161538 (Reactome)
ADPArrowR-HSA-2162092 (Reactome)
ADPArrowR-HSA-2162096 (Reactome)
AMPR-HSA-2161193 (Reactome)
ATPR-HSA-2161506 (Reactome)
ATPR-HSA-2161538 (Reactome)
ATPR-HSA-2162092 (Reactome)
ATPR-HSA-2162096 (Reactome)
Ade-RibArrowR-HSA-2161193 (Reactome)
GUK1mim-catalysisR-HSA-2162092 (Reactome)
H+ArrowR-HSA-2162078 (Reactome)
H2OR-HSA-2161195 (Reactome)
H2OR-HSA-2161506 (Reactome)
H2OR-HSA-2161538 (Reactome)
IMPR-HSA-2162066 (Reactome)
InoArrowR-HSA-2162066 (Reactome)
NAD+R-HSA-2162078 (Reactome)
NADHArrowR-HSA-2162078 (Reactome)
NT5C2 tetramermim-catalysisR-HSA-2162066 (Reactome)
PCK1mim-catalysisR-HSA-2162096 (Reactome)
PiArrowR-HSA-2161506 (Reactome)
PiArrowR-HSA-2161538 (Reactome)
R-HSA-2161193 (Reactome) Cytosolic adenosine phosphotransferase catalyzes the reaction of abacavir and AMP to form abacavir monophosphate and adenosine (Faletto et al. 1997). This enzymatic activity has been purified from human placenta and is distinct from known human kinases (Garvey and Krenitsky 1992) but has not been associated with a known human gene.
R-HSA-2161195 (Reactome) Cytosolic ADAL (Adenosine DeAminase-Like) catalyzes the reaction of abacavir monophosphate and water to form carbovir monophosphate and cyclopropylamine. The active form of the enzyme is a protein monomer complexed with a zinc ion (Murakami et al. 2011).
R-HSA-2161500 (Reactome) Organic cation transporters 1 (OCT1, SLC22A1), 2 (OCT2, SLC22A2) and 3 (OCT3, SLC22A3) associated with the plasma membrane all mediate the influx of abacavir. The three transporters have similar affinities for abacavir (Minuesa et al. 2009) but differ in the tissues in which they are expressed and in their distributions on the surfaces of polarized cells (reviewed by Klaasen and Aleksunes 2010).
R-HSA-2161506 (Reactome) ATP-binding cassette sub-family G member 2 (ABCG2), associated with the plasma membrane, mediates the ATP-dependent efflux of abacavir (Doyle et al. 1998). The active form of ABCG2 is a homodimer stabilized by an interchain disulfide bond (Wakabayashi et al. 2007). The abacavir specificity of the human ABCG2 transporter is inferred from studies of the corresponding mouse protein (Pan et al. 2007).
R-HSA-2161538 (Reactome) The ABCB1 transporter associated with the plasma membrane mediates the ATP-dependent efflux of a variety of xenobiotic molecules. Its ability to transport abacavir is inferred from studies of the corresponding mouse protein (Shaik et al. 2007).
R-HSA-2162066 (Reactome) NT5C2 catalyzes the reaction of carbovir and IMP to form carbovir monophosphate and inosine (Johnson and Fridland 1989; Miller et al. 1992). The enzyme was originally identified as a high-Km soluble 5'-nucleotidase most active on IMP and GMP (Spychala et al. 1988). Its active form is a tetramer (Wallden et al. 2007).
R-HSA-2162078 (Reactome) Cytosolic ADH alpha dimer catalyzes the reaction of abacavir and NAD to form abacavir 5'-carboxylate and NADH + H+. Abacavir 5'-carboxylate is one of the major forms in which abacavir is excreted from the body. Studies with purified enzymes in vitro indicate that only the alpha isoform of ADH has this activity. These studies also suggest that the reaction proceeds in two steps via an unstable aldehyde intermediate (Walsh et al. 2002). Whether conversion of the aldehyde to the carboxylate is spontaneous or also catalyzed by ADH has not been established.
R-HSA-2162092 (Reactome) Cytosolic GUK1 (guanylate kinase 1) catalyzes the reaction of carbovir monophosphate and ATP to form carbovir diphosphate and ADP. The activity of human GUK1 is inferred from that of the corresponding pig protein (Miller et al. 1992).
R-HSA-2162096 (Reactome) Cytosolic PCK1 (phosphoenolpyruvate carboxykinase 1) catalyzes the reaction of carbovir diphosphate and ATP to form carbovir triphosphate and ADP. The activity of human PCK1 and relative inactivity of human nucleoside diphosphate kinase are inferred from the properties of the purified rat and bovine enzymes in vitro (Miller et al. 1992).
R-HSA-2162099 (Reactome) A member of the UDPGT (UDP-glucuronosyltransferase) enzyme family is thought to catalyze the reaction of abacavir and UDP-glucuronate to form UDP and abacavir-5'-glucuronate, one of the major forms in which abacavir is excreted from the body (McDowell et al. 1999; Ravitch and Moseley 2001). The specific UDPGT family enzyme family member or members that catalyze this reaction have not been identified.
SLC22A1,2,3mim-catalysisR-HSA-2161500 (Reactome)
UDP-GlcAR-HSA-2162099 (Reactome)
UDPArrowR-HSA-2162099 (Reactome)
UDPGTmim-catalysisR-HSA-2162099 (Reactome)
abacavir 5'-carboxylic acidArrowR-HSA-2162078 (Reactome)
abacavir 5'-glucuronideArrowR-HSA-2162099 (Reactome)
abacavir monophosphateArrowR-HSA-2161193 (Reactome)
abacavir monophosphateR-HSA-2161195 (Reactome)
abacavirArrowR-HSA-2161500 (Reactome)
abacavirArrowR-HSA-2161506 (Reactome)
abacavirArrowR-HSA-2161538 (Reactome)
abacavirR-HSA-2161193 (Reactome)
abacavirR-HSA-2161500 (Reactome)
abacavirR-HSA-2161506 (Reactome)
abacavirR-HSA-2161538 (Reactome)
abacavirR-HSA-2162078 (Reactome)
abacavirR-HSA-2162099 (Reactome)
adenosine phosphotransferasemim-catalysisR-HSA-2161193 (Reactome)
carbovir monophosphateArrowR-HSA-2161195 (Reactome)
carbovir monophosphateArrowR-HSA-2162066 (Reactome)
carbovir monophosphateR-HSA-2162092 (Reactome)
carbovir triphosphateArrowR-HSA-2162096 (Reactome)
carbovir diphosphateArrowR-HSA-2162092 (Reactome)
carbovir diphosphateR-HSA-2162096 (Reactome)
carbovirR-HSA-2162066 (Reactome)
cyclopropylamineArrowR-HSA-2161195 (Reactome)
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