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(12) Patent Application Publication (10) Pub. No.: US 2017/0192012 A1 Martin Et Al

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US 201701920 12A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0192012 A1 Martin et al. (43) Pub. Date: Jul. 6, 2017 (54) COMPOSITIONS AND METHODS FOR (60) Provisional application No. 61/820,401, filed on May DETECTING S-NITROSYLATION AND 7, 2013. S-SULFNYLATION (71) Applicant: The Regents of the University of Publication Classification Michigan, Ann Arbor, MI (US) (51) Int. C. GOIN 33/68 (2006.01) (72) Inventors: Brent R. Martin, Ann Arbor, MI (US); (52) U.S. C. Jaimeen D. Majmudar, Ann Arbor, MI CPC ..... G0IN 33/6848 (2013.01); G0IN 2500/02 (US) (2013.01); G0IN 2440/26 (2013.01); G0IN (21) Appl. No.: 15/436,247 2440/30 (2013.01); G0IN 257.0/00 (2013.01) (22) Filed: Feb. 17, 2017 ABSTRACT Related U.S. Application Data (57) (63) Continuation of application No. 14/888,904, filed on The present invention relates to methods for detecting Nov. 3, 2015, filed as application No. PCT/US2014/ protein S-sulfinylation and S-sulfinylation within thiol 037111 on May 7, 2014. groups in proteins, metabolites, or materials. Patent Application Publication Jul. 6, 2017. Sheet 1 of 141 US 2017/0192012 A1 FG. A F.G. C FG D F.G. E. K. K.. -X-Biotit-SQ. YaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaBiotin-SQ. R3 : E3i:8888 88 i i ; : 2 283 kissee :3&tee 8w See Patent Application Publication Jul. 6, 2017. Sheet 2 of 141 US 2017/0192012 A1 FG 2 Reacter; Progress. Phery:s:::::ic Acid anchi-ke-8-stroso-Cys-Okie : Resententine initities: FG, 3 Penysulfiric Acid aid iodoacetatice 32 8. *s--c:r . !--- Bitter,i: , pri; 3. kic *8388x3s ^e * 5 hours 8 :::::::s::::::::::::::::283 is: 8. 3. Ketetion inns irates Patent Application Publication Jul. 6, 2017. Sheet 5 of 141 US 2017/0192012 A1 o-3-3-t --S s. (3 s'-ox 8 s sis." --- ... (88 k-, s s s -Xx & : 3- ---. i - '-- y Y-ch- is: 2 N- s &H 3 37 s 28 FIG. B. FG 7C ym Standard Curve (19) 7 : hiosulfonate Product, 3 34-Nie-Piloty's Acid, 28 y: 388x828: SO &s (3820: 1. s: S 40 3. 53 so 3. 33 Xtra 9:388) s so o Star&ard Curve (28 3. 2O 334:XX8. 3 y - 5333.8x + 3,343 O 28808 R-3.98882 i 8: - - 1 15 SS 4303 s 2. 3) 8. * }} E33 : GS80 : 4-Me-phenyisulfinic acid F.G. 8 233T Biotin-SOH (m8} 0 0 1 0.2 8.5 0.8 233 ki. 30 . 330 ... 75 80. 3 ... 20 - Patent Application Publication Jul. 6, 2017. Sheet 6 of 141 US 2017/0192012 A1 F.G. 9 emonoxBioti-SC).ht Hypotaurine (my) 5 50 25 ki 53 88. 37 F.G. 10 Biotin-SOH NO Donor fa-WA NONOate (nM} 0 1 20 50 00 500 250 k} - 33. 80. Patent Application Publication Jul. 6, 2017. Sheet 7 of 141 US 2017/0192012 A1 FG, Biotin-SOH Biotin-SOH 8 3. 8 s ii. S. 28 kw 233 ki wa 18 wer Sime 38 on 38 as Sween fSween 58 w Swan 28 w FG, 2. $3:38xixe:-38ky38 Akira-82cise s & 8 { a’ ? u Disciore-aikyte C s? C : N s {. r 8, C scoo FA&RA-azide of N-----Y. os---- Y Patent Application Publication Jul. 6, 2017. Sheet 8 of 141 US 2017/0192012 A1 F.G. 3 E g 3: s: Si:3. 3 33 250 kB - " 50 - O. Y- Nhi. 3-iodoacetaficie w 83 is -2.i tetramethylrhodamine-5-iodoacetamide (AA-AARA) FG, 14 1 mM Dimedone 5 mM Ascorbate 1 mM Peroxide sonM No Donor o5 mM Fluorescen-soH 0.5 mM FluorescensoH | | | | s vice ce::::::::: ce:: Patent Application Publication Jul. 6, 2017. Sheet 9 of 141 US 2017/0192012 A1 F.G. S Protein: Human GAPDH, recombinant Peptide: IISNASCTTNCLAPLAK Modification: C = carbamidomethyl, C* =S-S(O)-biotin (thiosulfonate-biotin) Retention Time: 44.70 minutes Drit Tie: 49.36 Betisie Charge: +3 Peptide M+H: 209.9885 y: y :::::sy: y: :: 3 4. S. y2 y: * - Easthanicionethy: C* : hiosier888-88tin Patent Application Publication Jul. 6, 2017. Sheet 10 of 141 US 2017/0192012 A1 F.G. 16 ax na go 2. | | | | s g | | | | 5 Protein Description swa s P23919 F & R Thymidylate kinase OOOOO 23 G.O 5 96.79.6 P25685 F & R | DnaJ homolog subfamily B member 1 OOOOO 22 O.OO 5 || 697497 O99428 F & R Tubulin-folding cofactor B OOOOO 20 OCO 5 224745 O9Y2O3 F & R Giutathione S-transferase kappa 1 OOOOO 20 O.OC 5 5545.2 P22090 F & R 40S ribosomal protein S4 00000 6 OOO 6 O.O p3909 F & R 40S ribosomal protein S19 OOOOO 5 O.800 4 205939.5 Q08257 F & R Qinore oxidoreductase 3000.00 5 0.00 A 0.0 Q9Y3B4 F & R | Pre-mRNA branch site protein p14 OOOOO || 4 || 000 || 6 90.383.0 P82244. F & R 40S ribosomal protein S5a OOOOO 13 OOO | 5 || 2471828 Q96CO F & R Protein FAM136A OOOOO 2 OOO 6 66O67.5 63.279 F & R SUMO-conjugating enzyme UBC9 100.00 2 OOO 3 O.O Q9UHC9 F & R NADH-cytochrome b5 reductase 1 100.00 2 0.00 3 O.O PO408O F & R Cystatin-B OOOOO 1 0.08 4 63616.5 Peptidyl-prolyl cis-trans isomerase F, p30405 F & R mitochondria 3000.00 9 O.OC 5 93663.8 P6956 F & R Snai tibiquitin-related modifier 2 3000.00 9 0.00 4 || 10132 Hydroxymethylglutary-CoA lyase, P35914. F & R mitochondria OOOOO 8 0.00 4 O.O 60981 F & R | Desti OOOOO || 8 || 000 4 46415.8 DNA-directed RNA polymerases , , P19388 & R and I subunit RPABC OOOOO 7 0.00 5 O.O Proteasome activator complex subunit Q946 F & R 2 OOOOO || 7 || OOO || 4 || 48029.6 Q15843 8. R NEDD8 1OOOOO 7 OOO 3 73965.8 Q96F2 & R Dynein light chain 2, cytoplasmic OOOOO 7 O.08 3 O.O 18077 F & R 60S ribosomal protein 35a 1OOOOO 5 OOO 5 913.20.8 Q005.26 F & R Cyclin-dependent kinase 3 OOOOO 5 O.00 3 O P55854 F & R Small ubiquitin-related modifier 3 OOOOO 4 OOO 4 O.O Q6EEV8 F&R Small ubiquitin-related modifier 4 OOOOO 4 OOO 4 O.O P300.50 F & R 60S ribosomal protein 12 O7.53 8 O.00 7 || 453842.8 O92526 F & R T-complex protein 1 subunit Zeta-2 55.35 O || 0 || 8 6363.2 Q9Y22 F & R Band 4.-like protein 3 5435 4 O.00 8 3243.3 12532 F & R Creatine kinase U-type, mitochondrial 52.91 8 O08 || 8 5902.0 P48643 F & R T-complex protein 1 subunit epsilon 49.95 12 0.08 8 || 336274.1 Patent Application Publication Jul. 6, 2017. Sheet 11 of 141 US 2017/0192012 A1 FIG. 6 (cont'd) Nuclear pore complex protein Nup98 P52948 F & R Nup96 49.75 14 O.O. 8 1565.4 Succinyl-CoA ligase ADP/GEDP p53597 F & R forming subunit alpha, mitochondrial 47.96 6 0.00 | f | 332458.3 C99623 & R Prohibitin-2 46.95 O O.00 8 446.2 p25398 F & R 40S ribosoma protein S12 46.2 14 0.00 || 8 || 48.7315.4 P32969 F & R 60S ribosomal protein 9 45.77 6 O.OO | 7 || 14205.5 Voltage-dependent anion-selective Ch9Y277 F & R channel protein 3 A444 12 O.OO 7 699049 26S proteasome non-ATPase OOO232 F & R regulatory subunit 32 44.25 8 O.OO 8 4211.6 P2A534 F & R Elongation factor 1-beta 43.38 6 O.OO || 8 || 734,476.4 Succinate dehydrogenase ubiquinone 3040 F & R favoprotein subunit, mitochondrial A3.05 9 O.OO | 8 || 27725.30 37.837 F & R Transacolase A2.55 4 O.OO | 8 || 153264 Pyruvate dehydrogenase E1 p 77 F & R component subunit beta, mitochondria 458 24 1.73 | 8 || 1284.75. P43686 F & R 26S protease regulatory subunit 68 A.0.6 8 0.00 | 8 || 220943.6 a 17987 F & R T-complex protein it subunit apha 39.62 3 O.OO | 8 || 40708 X-ray repair cross-complementing 1301 F & R protein 5 39.49 69 1.87 | 8 || 68.350.6 1553 F & R Nucleoside diphosphate kinase A 39.42 20 O.47 8 7488.6 P22392 F & R Nucleoside diphosphate kinase B 39.42 8 O.OO 8 8640.9 Regulator of chromosome 87.64 F & R condensation 38.74. 32 3.5 | 8 || 158947.4 4022 F & R T-complex protein it subuhit zeta 38.35 OO 1.62 | 8 || 50533.5 46782 F & R 40S ribosoma protein S5 38.31 4 O.OO | 8 || 28586.O. Ribosoma 1 domain-containing OFSO21 F & R protein 3.95 6 O.OO 8 158260.5 O43778 F & R Asparagine-tRNA ligase, cytoplasmic 37.7A. 6 O.OO | 8 || 0957.8 Putative nucleoside diphosphate O60361 F & R kinase 37.31 4 O.OO 6 56.9 Far upstream element-binding protein GR96AE4 F & R 1 37.07 20 O.OO | 8 || 159148.0 p7355 F & R Annexin A2 36.90 8 O.OO 8 21679. RNA-binding motif protein, X P38.59 F 8: R chronosome 36.63 24 0.00 8 7982O.9 4.6777 F & R 80S ribosoma protein 5 36.36 24 132 || 8 || 332370.3 10 kDa heat shock protein, 6604 r & R mitochondria 35.95 || 1 || 3 || 8 || 24623 O leucine-rich PPR motif-containing P42704 F & R protein, mitochondria 35.89 29 2.06 || 8 || 3O4909.3 P622A1 F & R 40S ribosoma protein S8 35.36 16 5.87 | 8 || 32754.5 Patent Application Publication Jul.
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