Supplementary data Investigation of the in vivo metabolism of sibirioside A and angoroside C in rats by HPLC-ESI-IT-TOF-MSn
Yi-Fan Zhang, Li-Jia Liu, Feng Xu, Ming-Ying Shang, Guang-Xue Liu,
Shao-Qing Cai
Division of Pharmacognosy, School of Pharmaceutical Sciences, Peking University Health Science Center, No.38, Xueyuan Road, Beijing 100191, China; [email protected] (Y.-F.Z.); [email protected] (L.-J.L.); [email protected] (F.X.); [email protected] (G.-X.L.); [email protected] (S.-Q.C.) * Correspondence: [email protected] (M.-Y.S.); Tel.: +86-10-8280-2534
Figure S1. The ESI-IT-TOF MSn spectra of angoroside C (A) and sibirioside A (B).
(x10,000,000) 229.0153 (1.00) 1.00 （A）
0.75
0.50
0.25
0.00 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x10,000,000) 229.0153 (1.00) 1.00 （B）
0.75 SM1
0.50
0.25
0.00 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S2. The negative ion mode EIC of SM1 in feces samples (A) blank group; (B) sibirioside A group. (x100,000) 259.0293 (1.00) 2.5 （A） 2.0
1.5
1.0
0.5
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x100,000) 259.0293 (1.00) 2.5 （B） 2.0
1.5 SM2
1.0
0.5
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S3. The negative ion mode EIC of SM2 in feces samples (A) blank group; (B) sibirioside A group.
(x100,000) 1.50 393.0838 (1.00)
1.25 （A）
1.00
0.75
0.50
0.25
0.00 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x100,000) 1.50 393.0838 (1.00)
1.25 （B） 1.00 SM3 0.75
0.50
0.25
0.00 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S4. The negative ion mode EIC of SM3 in feces samples (A) blank group; (B) sibirioside A group.
(x10,000) 633.2014 (1.00) 4.0 （A）
3.0
2.0
1.0
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x10,000) 633.2014 (1.00) 4.0 （B） SM4 3.0
2.0
1.0
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S5. The negative ion mode EIC of SM4 in stomach samples (A) blank group; (B) sibirioside A group.
(x100,000) 233.0119 (1.00) 4.0 （A） 3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x1,000,000) 233.0119 (1.00) 4.0 （B） 3.5 AM1 3.0
2.5
2.0
1.5
1.0
0.5
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S6. The negative ion mode EIC of AM1 in urine samples (A) blank group; (B) angoroside C group.
(x1,000,000) 242.9965 (1.00)
2.0 （A）
1.5
1.0
0.5
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x1,000,000) 242.9965 (1.00) 3.0 （B） 2.5 AM2
2.0
1.5
1.0
0.5
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S7. The negative ion mode EIC of AM2 in urine samples (A) blank group; (B) angoroside C group. (x1,000,000) 245.0109 (1.00) 8.0 （A） 7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x1,000,000) 245.0109 (1.00) 8.0 （B） 7.0 AM3 6.0
5.0
4.0
3.0
2.0
1.0
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S8. The negative ion mode EIC of AM3 in urine samples (A) blank group; (B) angoroside C group.
(x1,000,000) 247.0265 (1.00) 5.0 （A） 4.0
3.0
2.0
1.0
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x1,000,000) 247.0265 (1.00) 5.0 AM5 AM6 （B） 4.0 AM4 3.0
2.0
1.0
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S9. The negative ion mode EIC of AM4, AM5, AM6 in urine samples (A) blank group; (B) angoroside C group. (x100,000) 8.0 259.0271 (1.00) 7.0 （A） 6.0
5.0
4.0
3.0
2.0
1.0
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x100,000) 8.0 259.0271 (1.00) 7.0 （B） 6.0 AM7 5.0
4.0
3.0
2.0
1.0
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S10. The negative ion mode EIC of AM7 in urine samples (A) blank group; (B) angoroside C group.
(x1,000,000) 261.0051 (1.00) 3.5
3.0 （A）
2.5
2.0
1.5
1.0
0.5
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x1,000,000) 261.0051 (1.00) 3.5 （ ） 3.0 AM9 B
2.5 AM8
2.0
1.5
1.0
0.5
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S11. The negative ion mode EIC of AM8, AM9 in urine samples (A) blank group; (B) angoroside C group. (x1,000,000) 5.0 275.0210 (1.00) （A） 4.0
3.0
2.0
1.0
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x1,000,000) 5.0 275.0210 (1.00)
4.0 （B） AM10 3.0 AM11
2.0
1.0
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S12. The negative ion mode EIC of AM10, AM11 in urine samples (A) blank group; (B) angoroside C group.
(x1,000,000) 1.25 329.0817 (1.00) （A） 1.00
0.75
0.50
0.25
0.00 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x1,000,000) 1.25 329.0817 (1.00) （B） 1.00 AM13
0.75 AM14 0.50 AM12
0.25
0.00 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S13. The negative ion mode EIC of AM12, AM13, AM14 in urine samples (A) blank group; (B) angoroside C group. (x1,000,000) 341.0848 (1.00) 1.00 （A）
0.75
0.50
0.25
0.00 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x1,000,000) 341.0848 (1.00) 1.00 AM15 （B）
0.75
0.50
0.25
0.00 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S14. The negative ion mode EIC of AM15 in urine samples (A) blank group; (B) angoroside C group.
(x1,000,000) 343.1017 (1.00) 2.5 （A） 2.0
1.5
1.0
0.5
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x1,000,000) 343.1017 (1.00) 2.5 AM17 （B） 2.0
1.5
1.0 AM16
0.5
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S15. The negative ion mode EIC of AM16, AM17 in urine samples (A) blank group; (B) angoroside C group. (x100,000) 5.0 369.0794 (1.00) （ ） 4.0 A
3.0
2.0
1.0
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x100,000) 5.0 369.0794 (1.00) （ ） 4.0 B AM18 3.0
2.0
1.0
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S16. The negative ion mode EIC of AM18 in urine samples (A) blank group; (B) angoroside C group.
(x100,000) 371.0988 (1.00)
7.5 （A）
5.0
2.5
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x100,000) 371.0988 (1.00) （B） 7.5 AM19
5.0
2.5
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S17. The negative ion mode EIC of AM19 in urine samples (A) blank group; (B) angoroside C group. (x100,000) 637.2131 (1.00) 6.0 （A） 5.0
4.0
3.0
2.0
1.0
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x100,000) 637.2131 (1.00) 6.0 （B） 5.0 4.0 AM21 3.0 AM20
2.0
1.0
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S18. The negative ion mode EIC of AM20, AM21 in urine samples (A) blank group; (B) angoroside C group.
(x100,000) 959.3007 (1.00) 4.0 （A） 3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x100,000) 959.3007 (1.00) 4.0 （B） 3.5 AM22 3.0 2.5 AM23 2.0
1.5
1.0
0.5
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S19. The negative ion mode EIC of AM22, AM23 in urine samples (A) blank group; (B) angoroside C group. (x1,000,000) 461.1701 (1.00) 2.00
1.75 （A）
1.50
1.25
1.00
0.75
0.50
0.25
0.00 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x1,000,000) 461.1701 (1.00) 2.00
1.75 （B）
1.50 AM24
1.25
1.00
0.75
0.50
0.25
0.00 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S20. The negative ion mode EIC of AM24 in feces samples (A) blank group; (B) angoroside C group.
(x100,000) 2.5 247.0266 (1.00) （A） 2.0
1.5
1.0
0.5
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min
(x100,000) 2.5 247.0266 (1.00) （B） 2.0 AM25
1.5
1.0
0.5
0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 min Figure S21. The negative ion mode EIC of AM25 in feces samples (A) blank group; (B) angoroside C group. Table S1. The predict results of bioactivities for metabolites of sibirioside A and angoroside C. No. Target Score Potential Targets Potential Activities ID SM1 GTPase HRas Anti-cancer RASH 4.299 Anti myotrophic lateral 3.904 Angiogenin ANGI sclerosis Aldose reductase Anti-diabetes ALDR 3.821 Glucose-6-phosphate Nonspherocytic hemolytic 3.786 G6PI isomerase anemia Cathepsin K Osteogenic activity CATK 3.744 Nucleoside diphosphate Anti-cancer NDKB 3.730 kinase B Insulin receptor Anti-diabetes INSR 3.666 Pyruvate kinase PKLR Anti-hemolytic anemia KPYR 3.583 Bifunctional purine 3.582 Neuroprotective effect PUR9 biosynthesis protein SM2 GTPase HRas Anti-cancer RASH 5.549 Nucleoside diphosphate 4.580 Anti-cancer NDKB kinase B Aldose reductase Anti-diabetes ALDR 4.404 Pyruvate kinase PKLR Anti-hemolytic anemia KPYR 4.393 Bifunctional purine 4.212 Neuroprotective effect PUR9 biosynthesis protein Insulin receptor Anti-diabetes INSR 4.194 Anti myotrophic lateral 3.981 Angiogenin ANGI sclerosis Fibrinogen gamma chain Cardiovascular protection FIBG 3.840 Glucose-6-phosphate Nonspherocytic hemolytic 3.837 G6PI isomerase anemia Hepatocyte growth factor 3.778 Anti-cancer MET receptor Cathepsin K Osteogenic activity CATK 3.763 SM3 Pyruvate kinase PKLR Anti-hemolytic anemia KPYR 4.373 Tyrosine-protein kinase 4.288 Anti-chronic leukemia BTK BTK Coagulation factor VII Anti-coagulopathy FA7 4.144 Insulin receptor Anti-diabetes INSR 4.139 Aldose reductase Anti-diabetes ALDR 3.936 GTPase HRas Anti-cancer RASH 3.903 Bifunctional purine 3.885 Neuroprotective effect PUR9 biosynthesis protein Glucose-6-phosphate Nonspherocytic hemolytic 3.861 G6PI isomerase anemia Cathepsin K Osteogenic activity CATK 3.835 AM2 Nucleoside diphosphate 4.308 Anti-cancer NDKB kinase B GTPase HRas Anti-cancer RASH 4.219 Coagulation factor VII Anti-coagulopathy FA7 4.059 Bifunctional purine 4.152 Neuroprotective effect PUR9 biosynthesis protein Insulin receptor Anti-diabetes INSR 4.127 Pyruvate kinase PKLR Anti-hemolytic anemia KPYR 3.752 Carbonic anhydrase 2 Osteogenic activity CAH2 3.692 Anti-myotrophic lateral 3.616 Angiogenin ANGI sclerosis Tyrosine-protein kinase 3.613 Anti-chronic leukemia BTK BTK Angiotensin-converting 3.533 Cerebral protection ACE enzyme AM4 Nucleoside diphosphate 4.351 Anti-cancer NDKB kinase B Insulin receptor Anti-diabetes INSR 4.096 Anti myotrophic lateral 3.915 Angiogenin ANGI sclerosis Dual specificity 3.853 mitogen-activated protein Cardiovascular protection MP2K1 kinase kinase 1 Angiotensin-converting 3.815 Cerebral protection ACE enzyme Pyruvate kinase PKLR Anti-hemolytic anemia KPYR 3.780 Carbonic anhydrase 2 Osteogenic activity CAH2 3.714 GTPase HRas Anti-cancer RASH 3.714 Coagulation factor VII Anti-coagulopathy FA7 3.704 Serum albumin ALBU 3.518 AM5 Anti-myotrophic lateral 4.076 Angiogenin ANGI sclerosis Carbonic anhydrase 2 Osteogenic activity CAH2 3.878 Nucleoside diphosphate 3.837 Anti-cancer NDKB kinase B GTPase HRas Anti-cancer RASH 3.743 Bifunctional purine 3.706 Neuroprotective effect PUR9 biosynthesis protein Prothrombin Cerebrovascular protection THRB 3.683 Dual specificity 3.651 mitogen-activated protein Cardiovascular protection MP2K1 kinase kinase 1 Pyruvate kinase PKLR Anti-hemolytic anemia KPYR 3.617 Tyrosine-protein kinase 3.611 Anti chronic leukemia BTK BTK Insulin receptor Anti-diabetes INSR 3.600 AM6 Pyruvate kinase PKLR Anti-hemolytic anemia KPYR 4.501 Insulin receptor Anti-diabetes INSR 4.321 Coagulation factor VII Anti-coagulopathy FA7 4.104 Carbonic anhydrase 2 Osteogenic activity CAH2 3.810 Angiotensin-converting 3.763 Cerebral protection ACE enzyme Dual specificity 3.739 mitogen-activated protein Cardiovascular protection MP2K1 kinase kinase 1 Glucose-6-phosphate Nonspherocytic hemolytic 3.649 G6PD 1-dehydrogenase anemia AM8 Nucleoside diphosphate 4.434 Anti-cancer NDKB kinase B Tyrosine-protein kinase 4.410 Anti-chronic leukemia BTK BTK Anti-myotrophic lateral 4.246 Angiogenin ANGI sclerosis Pyruvate kinase PKLR Anti-hemolytic anemia KPYR 4.229 GTPase HRas Anti-cancer RASH 4.077 Inositol monophosphatase Anti-manic and 3.924 IMPA1 1 anti-depressant Carbonic anhydrase 2 Osteogenic activity CAH2 3.861 Glucose-6-phosphate Nonspherocytic hemolytic 3.844 G6PI isomerase anemia Fibrinogen gamma chain Cardiovascular protection FIBG 3.833 Bifunctional purine 3.704 Neuroprotective effect PUR9 biosynthesis protein AM9 Nucleoside diphosphate 4.397 Anti-cancer NDKB kinase B GTPase HRas Anti-cancer RASH 4.105 Anti myotrophic lateral 4.095 Angiogenin ANGI sclerosis Coagulation factor VII Anti-coagulopathy FA7 4.077 Bifunctional purine 4.046 Neuroprotective effect PUR9 biosynthesis protein Tyrosine-protein kinase 3.994 Anti-chronic leukemia BTK BTK Glucose-6-phosphate Nonspherocytic hemolytic 3.905 G6PD 1-dehydrogenase anemia Carbonic anhydrase 2 Osteogenic activity CAH2 3.810 Pyruvate kinase PKLR Anti-hemolytic anemia KPYR 3.797 Insulin receptor Anti-diabetes INSR 3.742 Fibrinogen gamma chain Cardiovascular protection FIBG 3.664 Mitogen-activated protein 3.653 Anti-epileptic encephalopathy MK10 kinase 10 Angiotensin-converting 3.629 Cerebral protection ACE enzyme AM10 Anti-myotrophic lateral 4.628 Angiogenin ANGI sclerosis GTPase HRas Anti-cancer RASH 4.482 Tyrosine-protein kinase 4.445 Anti-chronic leukemia BTK BTK Pyruvate kinase PKLR Anti-hemolytic anemia KPYR 4.253 Nucleoside diphosphate 4.083 Anti-cancer NDKB kinase B Coagulation factor VII Anti-coagulopathy FA7 3.995 Glucose-6-phosphate Nonspherocytic hemolytic 3.871 G6PI isomerase anemia Carbonic anhydrase 2 Osteogenic activity CAH2 3.832 Insulin receptor Anti-diabetes INSR 3.813 AM11 Nucleoside diphosphate 4.617 Anti-cancer NDKB kinase B Anti-myotrophic lateral 4.398 Angiogenin ANGI sclerosis GTPase HRas Anti-cancer RASH 4.269 Pyruvate kinase PKLR Anti-hemolytic anemia KPYR 4.248 Tyrosine-protein kinase 4.050 Anti-chronic leukemia BTK BTK Glucose-6-phosphate Nonspherocytic hemolytic 3.872 G6PI isomerase anemia cAMP-specific 3',5'-cyclic 3.848 Anti-stroke PDE4D phosphodiesterase 4D Carbonic anhydrase 2 Osteogenic activity CAH2 3.842 Insulin receptor Anti-diabetes INSR 3.773 AM12 GTPase HRas Anti-cancer RASH 4.089 Pyruvate kinase PKLR Anti-hemolytic anemia KPYR 3.795 Glucose-6-phosphate Nonspherocytic hemolytic 3.782 G6PD 1-dehydrogenase anemia Coagulation factor VII Anti-coagulopathy FA7 3.775 Inositol monophosphatase Anti-manic and 3.742 IMPA1 1 anti-depressant Aldose reductase Anti-diabetes ALDR 3.708 Ornithine 3.699 Anti-hyperornithinemia OAT aminotransferase Tyrosine-protein kinase 3.599 Anti-leukemias LCK Lck Dual specificity 3.529 mitogen-activated protein Cardiovascular protection MP2K1 kinase kinase 1 Glucose-6-phosphate Nonspherocytic hemolytic 3.496 G6PI isomerase anemia Serine--pyruvate 3.434 Anti-hyperoxaluria SPYA aminotransferase Insulin receptor Anti-diabetes INSR 3.432 Mitogen-activated protein 3.418 Anti-epileptic encephalopathy MK10 kinase 10 Angiogenin Anti-myotrophic lateral ANGI 3.384 sclerosis AM13 GTPase HRas Anti-cancer RASH 3.889 Coagulation factor VII Anti-coagulopathy FA7 3.591 Pyruvate kinase PKLR Anti-hemolytic anemia KPYR 3.468 Glucose-6-phosphate Nonspherocytic hemolytic 3.408 G6PD 1-dehydrogenase anemia Anti-myotrophic lateral 3.388 Angiogenin ANGI sclerosis Insulin receptor Anti-diabetes INSR 3.323 Mitogen-activated protein 3.246 Anti-epileptic encephalopathy MK10 kinase 10 Inositol monophosphatase Anti-manic and 3.156 IMPA1 1 anti-depressant Aldose reductase Anti-diabetes ALDR 2.992 Ornithine 2.970 Anti-hyperornithinemia OAT aminotransferase Complement C1s 2.910 Anti-autoimmune diseases C1S subcomponent cAMP-specific 3',5'-cyclic 2.906 Anti-stroke PDE4D phosphodiesterase 4D Catalase Anti-acatalasia CATA 2.896 Anti-dysalbuminemic 2.887 Serum albumin ALBU hyperthyroxinemia Prothrombin Anti-dysprothrombinemia THRB 2.884 AM14 GTPase HRas Anti-cancer RASH 3.770 Anti-myotrophic lateral 3.388 Angiogenin ANGI sclerosis Ornithine 3.338 Anti-hyperornithinemia OAT aminotransferase Coagulation factor VII Anti-coagulopathy FA7 3.316 Tyrosine-protein kinase 3.313 Anti-chronic leukemia BTK BTK Glucose-6-phosphate Nonspherocytic hemolytic 3.034 G6PD 1-dehydrogenase anemia Aldose reductase Anti-diabetes ALDR 2.992 Mitogen-activated protein 2.955 Anti-epileptic encephalopathy MK10 kinase 10 Transthyretin Anti-amyloidosis TTHY 2.952 Nucleoside diphosphate 2.946 Anti-cancer NDKB kinase B Carbonic anhydrase 2 Osteogenic activity CAH2 2.923 Complement C1s 2.910 Anti-autoimmune diseases C1S subcomponent Tyrosine-protein kinase Anti-leukemias LCK 2.868 Lck AM15 Insulin receptor Anti-diabetes INSR 5.223 Glucose-6-phosphate Nonspherocytic hemolytic 4.924 G6PI isomerase anemia GTPase HRas Anti-cancer RASH 4.901 Inositol monophosphatase Anti-manic and 4.873 IMPA1 1 anti-depressant Mitogen-activated protein 4.676 Anti-epileptic encephalopathy MK10 kinase 10 Tyrosine-protein kinase 4.390 Anti-leukemias LCK Lck Pyruvate kinase PKLR Anti-hemolytic anemia KPYR 4.333 Tyrosine-protein kinase 4.156 Anti-chronic leukemia BTK BTK Ornithine 4.117 Anti-hyperornithinemia OAT aminotransferase Anti myotrophic lateral 4.106 Angiogenin ANGI sclerosis Coagulation factor VII Anti-coagulopathy FA7 4.082 cAMP-specific 3',5'-cyclic 4.106 Anti-stroke PDE4D phosphodiesterase 4D AM18 Insulin receptor Anti-diabetes INSR 5.187 Inositol monophosphatase Anti-manic and 4.910 IMPA1 1 anti-depressant Tyrosine-protein kinase 4.874 Anti-chronic leukemia BTK BTK GTPase HRas Anti-cancer RASH 4.859 Mitogen-activated protein 4.627 Anti-epileptic encephalopathy MK10 kinase 10 Coagulation factor VII Anti-coagulopathy FA7 4.508 Glucose-6-phosphate Nonspherocytic hemolytic 4.497 G6PI isomerase anemia Angiotensin-converting 4.440 Cerebral protection ACE enzyme Ornithine 4.246 Anti-hyperornithinemia OAT aminotransferase Anti-myotrophic lateral 4.233 Angiogenin ANGI sclerosis AM19 Insulin receptor Anti-diabetes INSR 5.277 Inositol monophosphatase Anti-manic and 4.960 IMPA1 1 anti-depressant Tyrosine-protein kinase 4.865 Anti-chronic leukemia BTK BTK GTPase HRas Anti-cancer RASH 4.965 Mitogen-activated protein 4.540 Anti-epileptic encephalopathy MK10 kinase 10 Pyruvate kinase PKLR Anti-hemolytic anemia KPYR 4.484 Coagulation factor VII Anti-coagulopathy FA7 4.429 Anti-myotrophic lateral 4.258 Angiogenin ANGI sclerosis Glucose-6-phosphate Nonspherocytic hemolytic 4.168 G6PI isomerase anemia Aldose reductase Anti-diabetes ALDR 4.023 AM24 Tyrosine-protein kinase 3.786 Anti-chronic leukemia BTK BTK Insulin receptor Anti-diabetes INSR 3.753 GTPase HRas Anti-cancer RASH 3.499 Aldose reductase Anti-diabetes ALDR 3.210 Mitogen-activated protein 3.161 Anti-epileptic encephalopathy MK10 kinase 10 Carbonic anhydrase 2 Osteogenic activity CAH2 3.108 Prothrombin Cerebrovascular protection THRB 3.071 Coagulation factor VII Anti-coagulopathy FA7 3.053 Glucose-6-phosphate Nonspherocytic hemolytic 2.988 G6PD 1-dehydrogenase anemia AM25 GTPase HRas Anti-cancer RASH 4.556 Bifunctional purine 4.465 Neuroprotective effect PUR9 biosynthesis protein Insulin receptor Anti-diabetes INSR 4.264 Tyrosine-protein kinase 4.247 Anti-chronic leukemia BTK BTK Pyruvate kinase PKLR Anti-hemolytic anemia KPYR 4.161 Nucleoside diphosphate 4.144 Anti-cancer NDKB kinase B Angiotensin-converting 3.892 Cerebral protection ACE enzyme Inosine-5'-monophosphate 3.771 retinitis pigmentosa IMDH1 dehydrogenase 1 Glucose-6-phosphate Nonspherocytic hemolytic 3.749 G6PD 1-dehydrogenase anemia Signal transducer and 3.746 activator of transcription Immune related STAT1 1-alpha/beta