NADPH H2O CYP2A13 11DCORST H+ ADH1B CHOL3b,7a,25TRIOL H+ H2O Cu2+ (2Fe-2S)(1+) H2O CH2O 2CEO NADP+ PEA H+ H2O AOC3 H+ CYP3A5 Mg2+ 5HT 4-ethoxyaniline 20OH-TrXA3 O2 CYP2A13 FMO2 CYP2A13 HPHT H+ H2O MIND CYP2F1 NADPH TES O2 O2 CYP2F1 NADPH CYP11A1 4HPAA H2O FAD CYP2F1 O2 NH3 CHOL H2O CYP4F11 N-demethylated loperamide O2 H+ MAOA CYP2S1 12OH-DDCX H+ CH3COOH NASPM ARA CYP4A22 CYP2E1 PTGIS HBr NADPH H2O NADPH HDBQ H2O CYP2A7 PPi LCHA NADP+ H2O H+ NADP+ H+ CYP4F12 O2 CORT NADP+ 20OH-LTB4 4CHOL7a,12a,24(S)TONE NADP+ CYP2A13 27OH-CHOL CYP2A13 CYP11B2 7 alpha-hydroxycholesterol NAD+ CYP4F2 ATP H2O LPAM CYP2C8 H+ H+ EtO O2 NADP+ H2O CYP2C18 18OH-ARA H+ NADPH LTB4 CYP2C19 CYP4A11 O2 O2 AMP H2O CYP2C8 H+ 19HETE ADH1A CYP4A22 HCPM O2 CYP2D6 NADPH CYP27B1(?-508) The start coordinate is not yet known (Reactome) NADPH BEG e- CDL H2O H2O NADP+ CYP2E1 CYP2C9 CYP2E1 P4 AFB1 FAD H2O H+ CXPA Acetaminophen (TN TYLENOL) 4HPCP NADPH 5,6-EET CoA-SH ALDH1A1 H+ NADPH O2 NADPH H2O2 H+ CYP2J2 CYP7B1 CYP3A7 NADPH O2 H+ AADAC CYP2S1 NADP+ CYP2A13 CYP3A7 CYP39A1 acetyl group CYP4A22 heme b CYP1B1 NADP+ 25OH-CHOL CPM NADP+ O2 O2 NADPH NADP+ CYP4F12 NADP+ 14,15-EET NADPH 17aHPREG PTCN EtOH CYP2D6 FAD CYP4F22 H+ CYP24A1 NADP+ P22760 Uniprot O2 Ac-CoA H+ EST17b ACSS2 CYP1A2 H2O2 H+ H+ CYP2A6 CYP2B6 LNSOL CYP4F2 CYP3A43 O2 FMO3 NADPH CTLA Q16853 Uniprot CHEBI:17169 ChEBI SMOX-3 ALDH1B1 NH3 FDX1 CYP3A5 NADP+ CHEBI:8050 ChEBI CORST NADP+ P30837 Uniprot CHEBI:85505 ChEBI CHEBI:40574 ChEBI H+ CHEBI:17650 ChEBI CHEBI:1294 ChEBI CHEBI:34310 ChEBI CHEBI:16581 ChEBI H2O H+ O2 CHEBI:17813 ChEBI NADPH ALDH3A1 CYP2C9 CHEBI:17026 ChEBI NADP+ NADPH CHEBI:28694 ChEBI Q16850 Uniprot CHEBI:16469 ChEBI CHEBI:40538 ChEBI CYP2A7 CHEBI:62845 ChEBI O75106 Uniprot CHEBI:17500 ChEBI H+ CHEBI:16113 ChEBI CYP21A2 BZAL NADPH Oxindole PTGS1 NH3 NADP+ CHEBI:17263 ChEBI 4CHOL7aOLONE CHEBI:16474 ChEBI NADP+ CHEBI:15378 ChEBI CYP2S1 CHEBI:18009 ChEBI H2O CYP2A6 CYP2D6 NADP+ H+ CYP2W1 O2 NADPH H2O CHEBI:15552 ChEBI CYP11B2 CHEBI:15377 ChEBI CHEBI:16521 ChEBI P05093 Uniprot H2O CHEBI:42977 ChEBI H2O NADP+ CHEBI:37623 ChEBI H+ P05091 Uniprot NADPH CHEBI:15351 ChEBI CHEBI:15346 ChEBI CHEBI:16908 ChEBI CHEBI:30805 ChEBI O2 CHEBI:34157 ChEBI CHEBI:34130 ChEBI NADP+ CHEBI:34490 ChEBI ADH7 CHEBI:34450 ChEBI NADP+ O2 CHEBI:16973 ChEBI 4OH-atRA DSQ ACSS1 P00352 Uniprot CYP8B1 CHEBI:16236 ChEBI NADPH CYP17A1 H+ CHEBI:29888 ChEBI P07327 Uniprot 224930 PubMed Purification and partial characterization of aldehyde dehydrogenase from human erythrocytes. Inoue K, Nishimukai H, Yamasawa K. O2 TMA H+ Q9NR19 Uniprot NADPH CH3CHO H2O NADP+ NADP+ BZAM CHEBI:15366 ChEBI H2O NAD+ O2 P00326 Uniprot P00325 Uniprot P28332 Uniprot CYP4F3 P08319 Uniprot CYP4A11 MAOB CHEBI:15554 ChEBI CHEBI:10545 ChEBI CHEBI:29105 ChEBI P24557 Uniprot H2O ADH6 NCOA2 NADP+ O2 O2 H2O PhOH CHEBI:15647 ChEBI CHEBI:4470 ChEBI CHEBI:29133 ChEBI CYP2D6 6BHT CYP2C9 P40394 Uniprot CYP2C9 Q9NUB1 Uniprot MTZ-SOX H2 Ac-CoA NADPH S-HMGSH Ca2+ O75881 Uniprot CHEBI:26355 ChEBI P23219 Uniprot CYP4B1 P01189 Uniprot NADH CHEBI:15646 ChEBI CYP2J2 H2O CYP4B1 CYP4F2 TMAO HTOLB AOC1 CYP2D6 CHOL O2 CHEBI:27510 ChEBI CHEBI:63905 ChEBI O2 CHEBI:8107 ChEBI H+ CHEBI:63840 ChEBI CHEBI:6532 ChEBI P22680 Uniprot P20813 Uniprot P05181 Uniprot P10632 Uniprot P33261 Uniprot NADP+ H2O NABQI 3MEIN CHEBI:16842 ChEBI CHEBI:45863 ChEBI CHEBI:63804 ChEBI CYP2C18 CHEBI:30725 ChEBI NADPH CYP4B1 O2 H2O CHEBI:25858 ChEBI NADPH O2 P11712 Uniprot P10635 Uniprot Q96SQ9 Uniprot P24903 Uniprot P11509 Uniprot H2O H+ NADPH CYP4F2 CYP2E1 H2O 10843999 PubMed Molecular characterization of human acetyl-CoA synthetase, an enzyme regulated by sterol regulatory element-binding proteins. Luong A, Hannah VC, Brown MS, Goldstein JL. CHEBI:5615 ChEBI P05177 Uniprot CHEBI:1784 ChEBI H2O NADPH CHEBI:27732 ChEBI NH3 P33260 Uniprot CHEBI:16580 ChEBI Q9HB55 Uniprot H2O P20853 Uniprot Q16696 Uniprot CYP2E1 O2 INDOL O2 Q7Z449 Uniprot NADH CYP4F11 H2O CHEBI:27385 ChEBI TBXAS1 CHEBI:17996 ChEBI CHEBI:46195 ChEBI NADP+ CHEBI:29138 ChEBI CYP2E1 P13584 Uniprot NH3 H2O Q02928 Uniprot CHEBI:29129 ChEBI P51589 Uniprot NADPH Q8TAV3 Uniprot CYP2U1 H2O Q5TCH4 Uniprot H+ H+ P78329 Uniprot CHEBI:19138 ChEBI CHEBI:39567 ChEBI CYP2C18 CYP2A7 NADP+ CHEBI:63799 ChEBI H2O2 CYP11A1 CHEBI:63590 ChEBI NADPH CHEBI:17347 ChEBI CYP4F22 Q9Y6A2 Uniprot COUM CHEBI:17998 ChEBI H2O O2 CHEBI:17703 ChEBI Q08477 Uniprot CHEBI:28477 ChEBI NADP+ Q6NT55 Uniprot CHEBI:63839 ChEBI O2 P15538 Uniprot Q9HBI6 Uniprot H2O CHEBI:64043 ChEBI Zn2+ CHEBI:34477 ChEBI CHEBI:1864 ChEBI P04798 Uniprot CHEBI:27999 ChEBI 4CHOL7a,27DONE CHEBI:17899 ChEBI H+ CHEBI:48333 ChEBI MTZ CHEBI:63838 ChEBI CHEBI:15843 ChEBI CYP2D6 CHEBI:48825 ChEBI C2H4 NADPH CHEBI:4026 ChEBI CHEBI:63859 ChEBI CYP2C9 CHEBI:63800 ChEBI PREG H+ CES2 CHEBI:18153 ChEBI TYR CYP4F3 CYP2S1 CHEBI:34665 ChEBI H2O2 CHEBI:37640 ChEBI 11,12-EET NADP+ CHEBI:28750 ChEBI H2O CYP2R1 Q02318 Uniprot H2O NADP+ CHEBI:30751 ChEBI Q16678 Uniprot (2Fe-2S)2+ H+ CHEBI:9171 ChEBI C6H6 NADP+ CYP2A13 CHEBI:27561 ChEBI O2 CHEBI:28794 ChEBI O2 CHEBI:7772 ChEBI CHEBI:2504 ChEBI CHEBI:16422 ChEBI NADPH CH3COO- P11511 Uniprot 11DCORST NADPH P08686 Uniprot CHEBI:28324 ChEBI H2O Q9NYL5 Uniprot CYP4A11 FMO1 CYP2A6 CYP2E1 LTB4 CYP8B1 NADPH CYP2A7 H2O O2 CYP2C8 NADPH CYP4B1 H2O COCN TES Homo sapiens O2 Phase 1 - Functionalization of compounds Phase 1 of metabolism is concerned with <i><b>functionalization</b></i>, that is the introduction or exposure of functional groups on the chemical structure of a compound. This provides a 'handle' for phase 2 conjugating species with which to react with. Many xenobiotics are lipophilic and almost chemically inert (e.g. PAHs) so would not necessarily undergo a phase 2 reaction. Making them more chemically reactive would facilitate their excretion but also increases their chance of reacting with cellular macromolecules (e.g. proteins, DNA). There is a fine balance between producing a more reactive metabolite and conjugation reactions.<br>There are two groups of enzymes in phase 1 - oxidoreductases and hydrolases. Oxidoreductases introduce an oxygen atom into or remove electrons from their substrates. The major oxidoreductase enzyme system is called the P450 monooxygenases. Other systems include flavin-containing monooxygenases (FMO), cyclooxygenases (COX) and monoamine oxidases (MAO). Hydrolases hydrolyse esters, amides, epoxides and glucuronides. View original pathway at:[http://www.reactome.org/PathwayBrowser/#DIAGRAM=211945 Reactome]. (WikiPathways-description) H+ CHEBI:63912 ChEBI CHEBI:15379 ChEBI CYP2B6 CHEBI:15627 ChEBI ARA H+ CYP26B1 TAM 5HIALD CYP2C9 DEXM CH3CHO NADPH 3APAL H+ H+ H2O CYP2J2 CYP2B6 H2O CCl4 CYP2C19 CYP4F3 CHEBI:16716 ChEBI NADPH BaP4,5O NADPH CHEBI:28509 ChEBI CHEBI:47266 ChEBI R-NUL-76433 Reactome H2O CHEBI:18276 ChEBI H+ CYP2F1 NAD+ CYP2C19 H+ CHEBI:81621 ChEBI H2O2 CYP2A13 NADPH CYP11B1 P23141 Uniprot CHEBI:41001 ChEBI CHEBI:34560 ChEBI CYP46A1 O00748 Uniprot H+ H2O CYP4F2 CHEBI:27958 ChEBI CHOL CHEBI:17790 ChEBI CHEBI:196991 ChEBI NADPH CHEBI:3410 ChEBI CYP3A4 O2 P30838 Uniprot CYP2S1 H+ CYP2A7 CoA-SH NADH 20a,22b-DHCHOL ADH4 CYP2F1 CYP2A7 Cl- O2 NADPH CYP4A11 O2 H+ SPM H2O NADPH I4AH NADPH VC CYP2W1 CYP2C9 RXRA CYP2A13 H2O CHEBI:29108 ChEBI NADPH 4CHOL7a,24(S)DONE CHEBI:27398 ChEBI O2 O2 P19801 Uniprot HALO P07099 Uniprot AOC2 CHEBI:18295 ChEBI CYP2F1 O2 ATP NADP+ O2 CYP2B6 H2O O2 H+ ALDO CDCA NADPH PGH2 CYP4F11 NADP+ H+ 4CHOL7a,12a,27TONE CYP2F1 NADP+ CTL ADH1C P05108 Uniprot P22570 Uniprot H2O H2O P10109 Uniprot PHEN CHEBI:33738 ChEBI Q6P4F2 Uniprot CYP4B1 FAD NADP+ FAD CYP2B6 CES1 O43174 Uniprot NADP+ ALDH2 Q6V0L0 Uniprot Q9NR63 Uniprot O2 CHEBI:63802 ChEBI NADP+ CHEBI:50648 ChEBI 11DCORT CYP51A1 CYP27A1 Losec NADH H+ NADPH H+ CHEBI:83782 ChEBI NADPH CHEBI:48926 ChEBI H+ CTL CHEBI:15630 ChEBI BaP4,5-DHD CYP4F11 CHEBI:16225 ChEBI CHOL7a,24(S)DIOL P11766 Uniprot H2O CYP3A43 PGH2 H+ O2 4,4DMCHOLtrienol H2O CHEBI:16827 ChEBI CYP3A4 CHEBI:33737 ChEBI O2 CYP3A43 Q9NWM0-3 Uniprot CHEBI:27584 ChEBI CYP19A1 CHEBI:16485 ChEBI NADP+ CYP4F8 P19099 Uniprot P20815 Uniprot P08684 Uniprot P24462 Uniprot NADP+ CYP4F22 CYP2A6 H+ H2O2 CYP2A7 H+ FDX1L H+ ARA CYP4A11 FDX1L H2O NADP+ H2O Zn2+ 3,16DOH-PALM O2 CYP3A43 Ca2+ CYP2C8 CHEBI:16755 ChEBI NADPH Q15788 Uniprot Q15596 Uniprot 24OH-CHOL Q96RI1 Uniprot P19793 Uniprot H+ CHEBI:16325 ChEBI FDXR CYP26A1 CYP4F8 PTXL CYP2S1 H+ PAOX H+ H2O 12-HETE CYP2B6 PGI2 P98187 Uniprot O2 CHEBI:28834 ChEBI Q9UNU6 Uniprot Q16647 Uniprot Q9HCS2 Uniprot NADP+ O2 H+ NADPH NADP+ CYP26C1 O2 H2O CYP2E1 HOMZ NADP+ DCA E1 NADP+ AMP FDX1 O2 H2O H2O CYP2C9 NADP+ HCOOH NCOA1 O2 CYP7A1 NADPH CYP2F1 Hist O2 CYP7B1 ANDST O2 AFXBO H2O H+ CYP2J2 NADP+ CYP2C8 H2O2 NADP+ CYP2D6 ADH5 CYP2C8 CYP2C18 H2O NADP+ NADPH NHABP TAMO H+ CYP4A22 CYP2C19 CYP3A5 POMC(138-176) NADPH CHEBI:17823 ChEBI CYP4A22 NADP+ O15528 Uniprot 4065146 PubMed Mitochondrial aldehyde dehydrogenase from human liver. Primary structure, differences in relation to the cytosolic enzyme, and functional correlations. Hempel J, Kaiser R, Jörnvall H. CHEBI:15367 ChEBI ABPH CHEBI:63911 ChEBI PPi Q07973 Uniprot CAF NADPH CYP2C19 CYP2J2 CYP2C8 18HCORST CHEBI:63998 ChEBI NADPH CHEBI:63795 ChEBI NAD+ CHEBI:37248 ChEBI CHEBI:31697 ChEBI CHEBI:16881 ChEBI NADP+ S-FGSH O2 SPM NR1H4 O2 O2 CYP4F3 H2O O2 NADPH CYP2A7 CYP2B6 H+ FDXR CYP3A4 H+ CHEBI:15882 ChEBI CHEBI:28940 ChEBI CHEBI:29132 ChEBI Q6VVX0 Uniprot SPN 6BHT CHEBI:17933 ChEBI NADP+ H2O 18196 PubMed Two aldehyde dehydrogenases from human liver. Isolation via affinity chromatography and characterization of the isozymes. Greenfield NJ, Pietruszko R. O2 CYP4F11 MeOH DDCX O2 3AAPNAL HPHAC P27338 Uniprot P21397 Uniprot CHEBI:27647 ChEBI Q01740 Uniprot CYP2C8 24OH-CHOL CYP2C9 CHEBI:18420 ChEBI CYP2C19 NASPN H+ Trichloromethyl radical H+ 4OH-EST17b EPHX1 Phenytoin CHEBI:28790 ChEBI CYP3A7 CHEBI:15760 ChEBI CHEBI:15621 ChEBI CHEBI:16134 ChEBI CHEBI:16240 ChEBI CYP2C19 Cu2+ CH3CHO ISCAL NADPH TXA2 CYP2C8 CHEBI:63825 ChEBI CHEBI:15724 ChEBI CYP2C19 O2 CHEBI:18139 ChEBI H+ NADPH TFAC CHEBI:50673 ChEBI NADPH CHEBI:63904 ChEBI TrXA3 Paraxanthine CYP4F22 TYR CYP4F3 H2O CYP2S1 CHEBI:63828 ChEBI H2O DEXT Q99518 Uniprot CYP2A7 CHEBI:41774 ChEBI H+ H2O 4OH-9cRA CYP2C19 P31513 Uniprot CHEBI:16238 ChEBI O2 O2 NADP+ 3AAPNAL Q6QHF9 Uniprot 9cRA NADP+ H+ PGG2 O2 O2 CHEBI:15422 ChEBI CHEBI:15846 ChEBI CHEBI:16027 ChEBI PTGIS 3OH-PALM CHEBI:15343 ChEBI 20OH-LTB4 TBM H2O2 NADP+ 19OH-PGH2 NADPH NADPH 8,9-EET H2O HPTXL CYP4F8 atRA 4CHOL7a,12aDONE NH3 CYP4F2 H2O CH2O CYP26C1 PREG H2O2 CYP4F22 FAD CYP7A1 EtOH NADP+ CYP2F1 CYP2B6 Phenylacetaldehyde H2O CYP2S1 NADP+ CHEBI:18397 ChEBI CHEBI:50157 ChEBI CHEBI:17927 ChEBI O2 CHEBI:16424 ChEBI NADP+ HCOOH CHEBI:17312 ChEBI H2O H2O CYP4F2 H2O CHEBI:30322 ChEBI VD3 CYP4F22 CHEBI:15746 ChEBI H+ CHEBI:18090 ChEBI CHEBI:17148 ChEBI HCOU CHEBI:16610 ChEBI CYP1A1 CYP2E1