2457-80-9

Basic information

• Product Name: 5'-DEOXY-5'-METHYLTHIOADENOSINE
• Synonyms: 2-(6-aminopurin-9-yl)-5-(methylsulfanylmethyl)oxolane-3,4-diol;7-(5-Methylthio-5-deoxy-D-ribofuranosyl)-7H-purine-6-amine;7-[Tetrahydro-3α,4α-dihydroxy-5β-(methylthiomethyl)furan-2-yl]-7H-purin-6-amine;5'-S-Methyl-5'-thioadesine;5'-Deoxy-5'-(methylthio)adenosine ,98%;1-(6-AMino-9H-purin;5'-Deoxy(Methylthio)adenosine;NSC 335422
• CAS NO: 2457-80-9
• Molecular Formula: C₁₁H₁₅N₅O₃S
• Molecular Weight: 297.33
• Product Categories: Biochemicals and Reagents;Nucleoside Analogs;Nucleosides, Nucleotides, Oligonucleotides
• Mol File: 2457-80-9.mol
• Article Data: 17

Chemical Properties

• Melting Point: 210-213 °C (dec.)
• Boiling Point: 642.7°Cat760mmHg
• Flash Point: 342.5°C
• Appearance: /
• Density: 1.85g/cm³
• Storage Temp.: −20°C
• Solubility: DMF (Sparingly), DMSO (Slightly), Methanol (Slightly)
• PKA: 13.10±0.70(Predicted)
• BRN: 42420
• CAS DataBase Reference: 5'-DEOXY-5'-METHYLTHIOADENOSINE(CAS DataBase Reference)
• NIST Chemistry Reference: 5'-DEOXY-5'-METHYLTHIOADENOSINE(2457-80-9)
• EPA Substance Registry System: 5'-DEOXY-5'-METHYLTHIOADENOSINE(2457-80-9)

Safety Data

• Safety Statements: 22-24/25
• WGK Germany: 3
• RTECS: AU7410000
• F: 10-21
• Hazardous Substances Data: 2457-80-9(Hazardous Substances Data)

Usage

Uses

5′-Deoxy-5′-(methylthio)adenosine has been used as a protein methylation inhibitor to reduce E2F transcription factor 1 (E2F1) protein abundance in hepatocellular carcinoma (HCC) cells. It has also been used to inhibit histone methylation modification and study its role in hypoxia inducible factor-1 (Hif-1) nuclear transport.

Definition

ChEBI: Adenosine with the hydroxy group at C-5' substituted with a methylthio (methylsulfanyl) group.

Biological Activity

ki = 62 μm for s49-derived high-affinity camp phosphodiesterasemethylthioadenosine (mta) is a naturally occurring sulfur-containing nucleoside in all mammalian tissues. mta is mainly produced from s-adenosylmethionine via the polyamine biosynthetic pathway, behaving as a powerful inhibitory product.

Biochem/physiol Actions

5′-Deoxy-5′-(methylthio)adenosine (Methylthioadenosine) may be used as a substrate to study the specificity and kinetics of 5′-methylthioadenosinephosphorylase (MTAP) (EC2.4.2.28), a tumor suppressor gene expressed enzyme that supports the S-adenosylmethionine (AdoMet) and methionine salvage pathways.

in vitro

mta was found to be solely metabolized by mta-phosphorylase, to yield 5-methylthioribose-1-phosphate and adenine, which was a key step in methionine and purine salvage pathways, respectively. previous studies suggested that mta coud affect various cellular processes. mta had been shown to be albe to influence plenty of critical cell responses, such as proliferation, gene expression regulation, differentiation as well as apoptosis. though most of such responses had been only observed at the pharmacological level, their specificity made it tempting to speculate that endogenous mta might play a regulatory role in the cell [1].

in vivo

the hepatoprotective effects of mta had been evaluated in a model of ccl4-induced chronic liver damage in rats. in this study, mta could reproduce the human lesions induced by alcohol and viral infections of the liver. in addition, replenishment of the hepatic pool of mta showed strong anti-oxidant effects and also reduced liver cell damage and fibrosis [2].

Purification Methods

Recrystallise it from H2O and sublime it at 200o/0.004mm. [v.Euler & Myrb.ck Hoppe Seyler's Z physiol Chem 177 237 1928, Weygand & Trauth Chem Ber 84 633 1951, Baddiley et al. J Chem Soc 2662 1953.] The hydrochloride has m 161-162o [Kuhn & Henkel Hoppe Seyler's Z Physiol Chem 269 41 1941]. The picrate has m 183o(dec) (from H2O). [Beilstein 26 III/IV 3675.]

references

[1] avila ma,garcía-trevijano er,lu sc,corrales fj,mato jm. methylthioadenosine. int j biochem cell biol.2004 nov;36(11):2125-30.[2] pascale rm,simile mm,de miglio mr,feo f. chemoprevention of hepatocarcinogenesis: s-adenosyl-l-methionine. alcohol.2002 jul;27(3):193-8.

Synthetic route

methylthiol (74-93-1) + 5'-deoxy-5'-chloroadenosine (892-48-8) → 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide -30 deg C to r.t., overnight;	86%
With sodium hydroxide In methanol; water at 75℃; for 24h;	75%
With sodium hydride In N,N-dimethyl-formamide
With potassium tert-butylate In tetrahydrofuran; N,N-dimethyl-formamide at 40℃; for 12h;

5'-deoxy-5'-chloroadenosine (892-48-8) + sodium thiomethoxide (5188-07-8) → 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
In water at 75℃; for 24h;	65%
In N,N-dimethyl-formamide at 20℃;	50%

Dimethyldisulphide (624-92-0) + adenosine (58-61-7) → 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
With tributylphosphine In N,N-dimethyl-formamide for 240h;	38%

9-((3aR,4R,6S,6aS)-2,2-dimethyl-6-((methylthio)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (69660-30-6) → 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
With sulfuric acid
With sulfuric acid; acetone
With sulfuric acid; acetic acid

2',3'-Di-O-acetyl-5'-deoxy-5'-(methylthio)adenosine sulfoxide (119771-16-3) → 5'-Deoxy-5'-methylthioadenosine (2457-80-9) + 5'-Deoxy-5'-<(monofluoromethyl)thio>adenosine (118560-47-7) + 5'-Deoxy-5'-fluoro-5'-(methylthio)adenosine

Conditions	Yield
With dimethylaminosulphur trifluoride; ammonia 1) CHCl3, 55 deg C, 2.5-3 h, 2) MeOH, r.t., 2.5 h; Yield given. Multistep reaction. Yields of byproduct given;

[(2S,3S,4R,5R)-5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl]-[3-(2-hydroxy-phenyl)-3-methyl-butyl]-methyl-sulfonium (83332-24-5) → 4,4-dimethylchromane (40614-27-5) + 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
With acetate buffer In water at 40℃; pH 4 to 10;
With acetate buffer In water at 40℃; Mechanism; other oxyanion buffers; amine buffers;

[(2S,3S,4R,5R)-5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl]-[3-(2-hydroxy-phenyl)-3-methyl-butyl]-methyl-sulfonium (83332-24-5) → 5'-Deoxy-5'-methylthioadenosine (2457-80-9) + adenine (66224-66-6, 66224-67-7, 66224-68-8, 66224-69-9, 134434-48-3, 134434-49-4, 134454-76-5, 134461-75-9)

Conditions	Yield
With amine buffer In water at 40℃; pH > 10;

S-adenosyl-L-methionine → 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
With extractene from cultures of yeast
With aerobacter aerogenes

S-adenosyl-L-methionine → 5'-Deoxy-5'-methylthioadenosine (2457-80-9) + L-homoserine ; L-homoserine-lactone

Conditions	Yield
With water pH 4-6;

5'-chloro-5'-deoxy-2',3'-O-sulfinyladenosine (662131-88-6) → 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 98 percent / water; methanol / 20 °C 2: 50 percent / dimethylformamide / 20 °C View Scheme
Multi-step reaction with 2 steps 1: conc. aq. NH4OH / methanol / 1 h / Ambient temperature 2: 75 percent / NaOH / H2O; methanol / 24 h / 75 °C View Scheme

5'-deoxy-5'-chloroadenosine (892-48-8) → 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 2: acetate buffer / H2O / 40 °C / other oxyanion buffers; amine buffers View Scheme
Multi-step reaction with 2 steps 2: amine buffer / H2O / 40 °C / pH > 10 View Scheme

5’-deoxy-5’-methylsulfinyladenosine (3387-65-3) → 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 74 percent / 4-(dimethylamino)pyridine, Et3N / acetonitrile / 1 h 2: 1) (dimethylamino)sulfur trifluoride, 2) NH3 / 1) CHCl3, 55 deg C, 2.5-3 h, 2) MeOH, r.t., 2.5 h View Scheme

5'-chloro-5'-deoxy-2',3'-O-sulphinyladenosine hydrochloride (69260-62-4) → 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 94 percent / conc.NH4OH / methanol; H2O / 0.5 h / Ambient temperature 2: 86 percent / NaH / dimethylformamide / -30 deg C to r.t., overnight View Scheme

adenosine (58-61-7) → 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) SOCl2, pyridine, 2.) NH3 / 1.) acetonitrile, 2.) MeOH, H2O 2: NaH / dimethylformamide View Scheme
Multi-step reaction with 4 steps 1: unter Zusatz von ZnCl2 2: pyridine 3: DMF 4: aqueous H2SO4; acetic acid View Scheme
Multi-step reaction with 4 steps 1: unter Zusatz von ZnCl2 2: pyridine 3: acetone 4: aqueous H2SO4 View Scheme

2',3'-isopropylidene adenosine (362-75-4) → 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: pyridine 2: DMF 3: aqueous H2SO4; acetic acid View Scheme
Multi-step reaction with 3 steps 1: pyridine 2: acetone 3: aqueous H2SO4 View Scheme

((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 4-methylbenzenesulfonate (5605-63-0) → 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: DMF 2: aqueous H2SO4; acetic acid View Scheme
Multi-step reaction with 2 steps 1: acetone; dioxane 2: aqueous H2SO4; acetone View Scheme
Multi-step reaction with 2 steps 1: acetone 2: aqueous H2SO4 View Scheme

sodium salt of methanethiol + 5'-deoxy-5'-chloroadenosine (892-48-8) → 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
In N,N-dimethyl-formamide at 20℃; for 48h;

S-Adenosyl-L-methionine (14031-35-7, 17176-17-9, 29908-03-0, 75044-81-4, 78548-84-2, 79647-17-9, 91279-78-6) → L-2-aminobutyric acid (1492-24-6) + 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
With glycerol dehydratase activating enzyme aq. buffer; Enzymatic reaction;

L-methionine (63-68-3) + ATP (56-65-5) → S-Adenosyl-L-methionine (14031-35-7, 17176-17-9, 29908-03-0, 75044-81-4, 78548-84-2, 79647-17-9, 91279-78-6) + 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
With recombinant Methanocaldococcus jannaschii methionine adenosyltransferase; potassium chloride; magnesium chloride In aq. buffer at 65℃; for 4h; pH=8; Temperature; Reagent/catalyst; Enzymatic reaction;

L-methionine (63-68-3) + ATP (56-65-5) → 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
With hydrogenchloride; GLUTATHIONE; human methionine adenosyltransferase plasmid MATI; potassium chloride; magnesium chloride In aq. buffer at 23℃; for 0.333333h; pH=8; Catalytic behavior; Kinetics; Enzymatic reaction;
With methionine adenosyltransferase from Methanocaldococcus jannaschii In aq. buffer at 65℃; for 1h; pH=8; Reagent/catalyst; Enzymatic reaction;

C15H19N5O5S → 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
With Pyrococcus horikoshii Dph2; dithionite(2-) In aq. acetate buffer at 20℃; for 0.333333h; pH=7.4; Inert atmosphere; Enzymatic reaction;

adenosine (58-61-7) + sodium thiomethoxide (5188-07-8) → 5'-Deoxy-5'-methylthioadenosine (2457-80-9)

Conditions	Yield
Stage #1: adenosine With thionyl chloride Stage #2: sodium thiomethoxide

5'-Deoxy-5'-methylthioadenosine (2457-80-9) + 2,2-dimethoxy-propane (77-76-9) → 9-((3aR,4R,6S,6aS)-2,2-dimethyl-6-((methylthio)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (69660-30-6)

Conditions	Yield
With toluene-4-sulfonic acid In acetone at 20℃; for 2h;	99%

acetic anhydride (108-24-7) + 5'-Deoxy-5'-methylthioadenosine (2457-80-9) → 2',3'-Di-O-acetyl-5'-deoxy-5'-(methylthio)adenosine (119771-17-4)

Conditions	Yield
With pyridine at 0℃; for 7h;	98%
With pyridine at 0 - 10℃; for 6h;	87%
With dmap; triethylamine In acetonitrile for 1h; Ambient temperature;	78%
With dmap; triethylamine In acetonitrile for 1h;	75%

5'-Deoxy-5'-methylthioadenosine (2457-80-9) → 5'-deoxy-5'-methylthioinosine

Conditions	Yield
With adenylate deaminase; dimethyl sulfoxide In phosphate buffer for 0.05h; pH=6.5;	95%

5'-Deoxy-5'-methylthioadenosine (2457-80-9) → 5'-S-methyl-5'-thioinosine (17298-58-7)

Conditions	Yield
With phosphate buffer pH 6.8; ethanethiol In water α-amylase from Aspergillus oryzae;	93%
With acetic acid; sodium nitrite
With adenosine deaminase from Plasmodium falciparum In phosphate buffer at 30℃; pH=7.0; Enzyme kinetics; Enzymatic reaction;

4-bromocrotonic acid (13991-36-1, 20629-35-0) + 5'-Deoxy-5'-methylthioadenosine (2457-80-9) → C15H19N5O5S

Conditions	Yield
With formic acid; silver perchlorate; acetic acid at 0 - 20℃; for 5.33333h;	87%

5'-Deoxy-5'-methylthioadenosine (2457-80-9) + benzoyl chloride (98-88-4) → C39H31N5O7S (153815-18-0)

Conditions	Yield
With pyridine for 16h; Ambient temperature;	85%

5'-Deoxy-5'-methylthioadenosine (2457-80-9) + methyl iodide (74-88-4) → dimethyl(5'-adenosyl)sulfonium perchlorate

Conditions	Yield
With formic acid for 72h; Ambient temperature;	84.1%

5'-Deoxy-5'-methylthioadenosine (2457-80-9) → 5'-deoxyadenosine (4754-39-6)

Conditions	Yield
With hydrogen; nickel In water at 90℃; under 3102.9 Torr; for 48h;	83%

methyl bromide (74-83-9) + 5'-Deoxy-5'-methylthioadenosine (2457-80-9) → 5'-deoxy-5'-dimethylsulfunioadenosine bromide (1106914-63-9)

Conditions	Yield
In formic acid; diethyl ether; acetic acid at 20℃; for 144h; Darkness;	65%

5'-Deoxy-5'-methylthioadenosine (2457-80-9) + carbonochloridic acid, butyl ester (592-34-7) → N-(butoxycarbonyl)-2′,3′-bis(butylcarbonate)-5′-methylthioadenosine

Conditions	Yield
Stage #1: 5'-Deoxy-5'-methylthioadenosine With 1-methyl-1H-imidazole In dichloromethane at 0℃; for 0.0833333h; Stage #2: carbonochloridic acid, butyl ester In dichloromethane at 0 - 20℃; for 72h;	65%

n-hexyl chloroformate (6092-54-2) + 5'-Deoxy-5'-methylthioadenosine (2457-80-9) → N-(hexoxycarbonyl)-2′,3′-bis(hexylcarbonate)-5′-methylthioadenosine

Conditions	Yield
Stage #1: 5'-Deoxy-5'-methylthioadenosine With 1-methyl-1H-imidazole In dichloromethane at 0℃; for 0.0833333h; Stage #2: n-hexyl chloroformate In dichloromethane at 0 - 20℃; for 72h;	61%

chloroformic acid ethyl ester (541-41-3) + 5'-Deoxy-5'-methylthioadenosine (2457-80-9) → N-(ethoxycarbonyl)-2′,3′-bis(ethylcarbonate)-5′-methylthioadenosine

Conditions	Yield
Stage #1: 5'-Deoxy-5'-methylthioadenosine With 1-methyl-1H-imidazole In dichloromethane at 0℃; for 0.0833333h; Stage #2: chloroformic acid ethyl ester In dichloromethane at 0 - 20℃; for 72h;	57%

2-Methoxyethyl chloroformate (628-12-6) + 5'-Deoxy-5'-methylthioadenosine (2457-80-9) → N-(2-methoxyethyoxy)carbonyl-2′,3′-bis(2-methoxyethylcarbonate)-5′-methylthioadenosine

Conditions	Yield
Stage #1: 5'-Deoxy-5'-methylthioadenosine With 1-methyl-1H-imidazole In dichloromethane at 0℃; for 0.0833333h; Stage #2: 2-Methoxyethyl chloroformate In dichloromethane at 0 - 20℃; for 72h;	56%

5'-Deoxy-5'-methylthioadenosine (2457-80-9) + isopropyl chloroformate (108-23-6) → N-(isopropoxycarbonyl)-2′,3′-bis(isopropylcarbonate)-5′-methylthioadenosine

Conditions	Yield
Stage #1: 5'-Deoxy-5'-methylthioadenosine With 1-methyl-1H-imidazole In dichloromethane at 0℃; for 0.0833333h; Stage #2: isopropyl chloroformate In dichloromethane at 0 - 20℃; for 72h;	52%

5'-Deoxy-5'-methylthioadenosine (2457-80-9) + propoxycarbonyl chloride (109-61-5) → N-(propoxycarbonyl)-2′,3′-bis(propylcarbonate)-5′-methylthioadenosine

Conditions	Yield
Stage #1: 5'-Deoxy-5'-methylthioadenosine With 1-methyl-1H-imidazole In dichloromethane at 0℃; for 0.0833333h; Stage #2: propoxycarbonyl chloride In dichloromethane at 0 - 20℃; for 72h;	46%

5'-Deoxy-5'-methylthioadenosine (2457-80-9) → (2S,3R,4S,5S)-2-Methoxy-5-methylsulfanylmethyl-tetrahydro-furan-3,4-diol + (2R,3R,4S,5S)-2-Methoxy-5-methylsulfanylmethyl-tetrahydro-furan-3,4-diol

Conditions	Yield
With trifluoroacetic acid In methanol Heating;	A 15% B 40%

5'-Deoxy-5'-methylthioadenosine (2457-80-9) + p-toluenesulfonyl chloride (98-59-9) → S-methyl-N6,O2',O3'-tris-(toluene-4-sulfonyl)-5'-thio-adenosine (80860-53-3)

Conditions	Yield
With pyridine

5'-Deoxy-5'-methylthioadenosine (2457-80-9) + methyl iodide (74-88-4) → 5'-(dimethylsulfonio)-5'-deoxyadenosine iodide (81162-88-1)

Conditions	Yield
With acetic acid
With formic acid
With formic acid at 40℃;

5'-Deoxy-5'-methylthioadenosine (2457-80-9) → S-methyl-5-thio-D-ribose (23656-67-9)

Conditions	Yield
With sulfuric acid
With hydrogenchloride

5'-Deoxy-5'-methylthioadenosine (2457-80-9) → 9-((3aR,4R,6S,6aS)-2,2-dimethyl-6-((methylthio)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (69660-30-6)

Conditions	Yield
With acetone; zinc(II) chloride

acetic anhydride (108-24-7) + 5'-Deoxy-5'-methylthioadenosine (2457-80-9) → 2',3'-Di-O-acetyl-5'-deoxy-5'-(methylthio)adenosine sulfoxide (119771-16-3)

Conditions	Yield
With pyridine; 3-chloro-benzenecarboperoxoic acid 2.) CH2Cl2, -40 deg C; Multistep reaction;

Upstream product

• 69660-30-6 9-((3aR,4R,6S,6aS)-2,2-dimethyl-6-((methylthio)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine 
• 119771-16-3 2',3'-Di-O-acetyl-5'-deoxy-5'-(methylthio)adenosine sulfoxide 
• 69260-62-4 5'-chloro-5'-deoxy-2',3'-O-sulphinyladenosine hydrochloride 
• 63-68-3 L-methionine 
• 56-65-5 ATP 
• 74-93-1 methylthiol 
• 892-48-8 5'-deoxy-5'-chloroadenosine 
• 58-61-7 adenosine 
• 5188-07-8 sodium thiomethoxide 
• 14031-35-7 S-Adenosyl-L-methionine 
• 5605-63-0 ((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 4-methylbenzenesulfonate 
• 362-75-4 2',3'-isopropylidene adenosine 
• 3387-65-3 5’-deoxy-5’-methylsulfinyladenosine 
• 662131-88-6 5'-chloro-5'-deoxy-2',3'-O-sulfinyladenosine 

Downstream Products

• 80860-53-3 S-methyl-N⁶,O^2'_,O3'-tris-(toluene-4-sulfonyl)-5'-thio-adenosine 
• 23656-67-9 S-methyl-5-thio-D-ribose 
• 17298-58-7 5'-S-methyl-5'-thioinosine 
• 3387-65-3 5’-deoxy-5’-methylsulfinyladenosine 
• 5143-04-4 5'-Deoxy-5'-methylsulphonyladenosine 
• 66224-66-6 adenine 
• 73-24-5 7H-purin-6-ylamine 
• 153815-19-1 N⁶,N⁶-dibenzoyl-2',3'-O-dibenzoyl-5'-deoxy-5'-fluoromethylthioadenosine 
• 4754-39-6 5'-deoxyadenosine 
• 153815-18-0 C₃₉H₃₁N₅O₇S 

Relevant articles and documents

Engineered SAM Synthetases for Enzymatic Generation of AdoMet Analogs with Photocaging Groups and Reversible DNA Modification in Cascade Reactions

Methylation and demethylation of DNA, RNA and proteins has emerged as a major regulatory mechanism. Studying the function of these modifications would benefit from tools for their site-specific inhibition and timed removal. S-Adenosyl-L-methionine (AdoMet) analogs in combination with methyltransferases (MTases) have proven useful to map or block and release MTase target sites, however their enzymatic generation has been limited to aliphatic groups at the sulfur atom. We engineered a SAM synthetase from Cryptosporidium hominis (PC-ChMAT) for efficient generation of AdoMet analogs with photocaging groups that are not accepted by any WT MAT reported to date. The crystal structure of PC-ChMAT at 1.87 ? revealed how the photocaged AdoMet analog is accommodated and guided engineering of a thermostable MAT from Methanocaldococcus jannaschii. PC-MATs were compatible with DNA- and RNA-MTases, enabling sequence-specific modification (“writing”) of plasmid DNA and light-triggered removal (“erasing”).

SELECTIVE INHIBITORS OF PROTEIN ARGININE METHYLTRANSFERASE 5 (PRMT5)

The disclosure is directed to compounds of Formula (I) and Formula (II). Methods of their use and preparation is other described.

Organometallic Complex Formed by an Unconventional Radical S-Adenosylmethionine Enzyme

Pyrococcus horikoshii Dph2 (PhDph2) is an unusual radical S-adenosylmethionine (SAM) enzyme involved in the first step of diphthamide biosynthesis. It catalyzes the reaction by cleaving SAM to generate a 3-amino-3-carboxypropyl (ACP) radical. To probe the reaction mechanism, we synthesized a SAM analogue (SAMCA), in which the ACP group of SAM is replaced with a 3-carboxyallyl group. SAMCA is cleaved by PhDph2, yielding a paramagnetic (S = 1/2) species, which is assigned to a complex formed between the reaction product, α-sulfinyl-3-butenoic acid, and the [4Fe-4S] cluster. Electron-nuclear double resonance (ENDOR) measurements with 13C and 2H isotopically labeled SAMCA support a π-complex between the C=C double bond of α-sulfinyl-3-butenoic acid and the unique iron of the [4Fe-4S] cluster. This is the first example of a radical SAM-related [4Fe-4S]+ cluster forming an organometallic complex with an alkene, shedding additional light on the mechanism of PhDph2 and expanding our current notions for the reactivity of [4Fe-4S] clusters in radical SAM enzymes.