Minjia Tan, Ph.D Shanghai Institute of Materia Medica, Chinese Academy of Sciences

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1 Lysine Glutarylation Is a Protein Posttranslational Modification Regulated by SIRT5 Minjia Tan, Ph.D Shanghai Institute of Materia Medica, Chinese Academy of Sciences

2 Lysine: the most frequently modified amino acid PTMs on the lysine residue: Acetylation, ubiquitylation, methylation, propionylation. Acetyl Succinyl Tri-methyl Malonyl Lysine Ubiquitinyl Crotonyl Tan et al, Cell : Zhang and Tan et al Nature Chem Biol : Peng et al, Mol Cell Proteomics M

3 The Ksucc proteome in mammalian cell 2,565 Ksucc sites on 779 proteins. Kim et al, Mol Cell :919-30

4 Proteome-wide E. Coli Ksucc Substrates Biological Process translation oxo acid metabolism cellular ketone metabolism cellular amino acid metabolism nucleotide metabolism gene expression Log 10 Adj P 2487 Ksucc sites on 658 proteins ~16% E. coli proteome CobB is a desuccinylase and deacetylase Gozde, Tan et al. Mol Cell Proteomics. 2013,

5 Lysine glutarylation (Kglu) Da Da + 86 Da

6 Detection of Kglu signals by anti-kglu antibody -250kd -150kd Kglu Ksucc Kmal Kac K -100kd 1x -75kd IB: K glu 5x IB: K glu -50kd -37kd 25x -25kd -20kd Dot spot assay Competed with unmodified BSA tryptic peptides Competed with glutarylated-bsa tryptic peptides -15kd -10kd

7 Identification of Kglu peptides by MS HeLa digestion IP HPLC/MS/MS Kglu (+114 Da) peptides identified by MS from HeLa cells. Peptide Sequence Protein Name Site NFSTVDIQKNGVK DNA mismatch repair protein Msh2 K546 TVDGPSGKLWR Glyceraldehyde- 3- phosphate dehydrogenase K194 VGMGGMEAKVK Delta- 1- pyrroline- 5- carboxylate synthase K311 SDVYYFSPSGKK Methyl- CpG- binding domain protein 2 K185 ADGKISEQSDAK ATP synthase subunit alpha K531 TPVTDPATGAVKEK Very- long- chain specific acyl- CoAdehydrogenase K322 VIQGAGKLPR Zinc finger/btb domain- containing protein 7A K396 NFGTKISAR 6- phosphofructokinase type C K688 GKGGEIQPVSVK 10 kda heat shock protein K56 FASDPIIKGSGTAEVELK Pyruvate kinase K105 MS/MS

8 Validation of Kglu 1. MS/MS analysis 2. HPLC Co-elution 100 NFSTVDIQK glu NGVK Synthetic Synthetic z= y 11 y 10 y 9 y 8 y 7 y 5 y 4 N F S T V D I Q K glu N G V K b 2 b In vivo In Vivo z=2 y y 7 b 2 y 4 y y 11 y y y Mixture Time (min)

9 Validation of Kglu 3. In vivo D4-glutrate labeling Glutarate Glutarate Glutarate Anti-K glu -200kDa -150kDa -100kDa -75kDa -50kDa -37kDa -25kDa -20kDa -15kDa -10kDa Anti-K ac -200kDa -150kDa -100kDa -75kDa -50kDa -37kDa -25kDa -20kDa -15kDa -10kDa Coomassie Blue -200kDa -150kDa -100kDa -75kDa -50kDa -37kDa -25kDa -20kDa -15kDa -10kDa 100 y y 12 y 11 y 10 y 9 y 8 y 7 y 6 y 5 N F S T V D I Q K 4D-Glu y 4 y 3 N G V K b 2 b 3 b 4 b 5 b 6 b 8 b 12 0 b y b * y * * b y b y y b y y y m/z b y *

10 What is the regulatory enzyme?

11 Screening regulatory enzymes for dekglu HC Acyllysine compound based assay HN NH H N HDACs Boc-Lys(glutaryl)-AMC Fluorescence (AU x10 5 ) µg Protein 2 µg Protein NH H N Boc-Lys-AMC 0 SIRT1 SIRT2 SIRT3 SIRT4 SIRT5 SIRT6 SIRT7 H 2 N Trypsin NH H 2 N 4-Amino-methylcoumarin fluorescence,30-folds (Ex=390nm,Em=460nm) H 2 N

12 SIRT5 as a dekglu enzyme in vitro 32 P-NAD + consumption assay Kglu peptide assay NAD + mau : VKSKATNLWW : VKSK glu ATNLWW z=2 613 m/z z=2 670 m/z Sirt5 +Sirt5 +Sirt5- HY Sirt5 - NAD 0 o-glutaryl-adp ribose, G-ADPR; o-succinyl-adp ribose, S-ADPR; o-acetyl-adp ribose, A-ADPR Sirt5 +NAM +Sirt5 +Sirtinol +Sirt5 +TSA +Sirt5 +NaBu min

13 SIRT5 catalyzes dekglu in vivo Pair 1 Pair 2 Pair 3 Pair 1 Pair 2 Pair 3 Pair 1 Pair 2 Pair 3-200kDa -150kDa -100kDa -75kDa -50kDa -37kDa -25kDa -20kDa -15kDa -200kDa -150kDa -100kDa -75kDa -50kDa -37kDa -25kDa -20kDa -15kDa -200kDa -150kDa -100kDa -75kDa -50kDa -37kDa -25kDa -20kDa -15kDa -10kDa -10kDa -10kDa Coomassie Blue Anti-K glu Anti-K succ Mitochondrial lysates from WT and Sirt5 K mouse livers

14 Sirt5 is the regulatory enzyme for Kmal/Ksucc Lysine Peng et al, Mol Cell Proteomics. 2011,,M

15 What are the preferred deacylation susbtrates of SIRT5?

16 Kinetic studies for SIRT5 deacylation activity

17 In silico molecular modeling K glu K mal K succ K adi K ac

18 Lys Acylation and Sirtuins Mann M., et al, Nat Rev Mol Cell Biol Aug;15:

19 Physiological significane of Kglu?

20 Biosynthetic Pathway of Glutaryl-CoA

21 Protein hyperglutarylation is sensitive to dietary changes Coomassie Blue Anti-K ac Anti-K glu The effect of tryptophan on the Kglu levels of Drosophila

22 Protein hyperglutarylation is sensitive to dietary changes Set 1 Set 2 Anti-K glu Lysate from WT and Sirt5 K 48h-fed and fasted mice livers.

23 Proteome-wide survey of Kglu sites in SIRT5K mouse liver 683 Kglu sites in 191 proteins Carbamoyl-phosphate synthetase 1 氨甲酰磷酸合成酶 (CPS1): 33 Kglu sites Key enzyme for ammonia detoxification

24 CPS1 is targeted for dekglu by SIRT5

25 Candidate Kglu sites regulated by SIRT5 Chemical glutarylated CPS1 Kglu site Peptide Sequence SIRT5 SIRT5 In vivo - + K55 AQTAHIVLEDGTKMK Yes No Yes K219 GNPTKVVAVDCGIK Yes No Yes K412 ATTITSVLPKPALVASR Yes No Yes K889 DILNMEKTLK Yes No Yes K892 TLKGLNSESMTEETLK Yes No Yes K915 AKEIGFSDKQISK Yes No Yes K1360 IPQKGILIGIQQSFRPR Yes No Yes K1486 KVDSKSLFHYR Yes No Yes

26 Structural analysis on glutarylated CPS1 homology model allosteric activation K1486 CPS1 oligomerization domain glutamine amidotransferase domain (structurally and interaction)

27 Pathological singnificance of Kglu?

28 Biosynthetic Pathway of Glutaryl-CoA human glutaric acidemia I

29 Protein hyperglutarylation in GCDH deficient mouse A A B K glu C

30 Kglu and Glutaric Acidemia I (GA) Crotonyl-CoA Tan et al, Cell Metabolism, 2014, 19,

31 Acknowledgements Prof. Zhao s Lab Chao Peng Zhonyu Xie Lunzhi Dai Gozde Colak Hao Luo Sangkyu Lee Prof. Matt Hirschey Prof. David Lombard

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