Adenosylmethionine decarboxylase (prokaryotic)

 

S-adenosylmethionine decarboxylase (AdoMetDC) isolated from Thermotoga maritima is an enzyme that catalyses the decarboxylation of S-adenosylmethionine (AdoMet or SAM) to S-adenosyl-5'-(3-methylthiopropylamine) (dcAdoMet). AdoMetDC is regulatory enzyme in the biosynthesis of spermine and spermidine. It is a class 1B AdoMetDC and belongs to a small family of decarboxylating enzymes that act on amino acids using bound pyruvate as an electron sink. AdoMetDC is synthesised as a proenzyme and must undergo self-maturation by nonhydrolytic serinolysis. It is during this process that the pyruvate group is formed at the carboxy terminus of the alpha chain.

 

Reference Protein and Structure

Sequence
Q9WZC3 UniProt (4.1.1.50) IPR017716 (Sequence Homologues) (PDB Homologues)
Biological species
Thermotoga maritima MSB8 (Bacteria) Uniprot
PDB
1vr7 - Crystal structure of S-adenosylmethionine decarboxylase proenzyme (TM0655) from THERMOTOGA MARITIMA at 1.2 A resolution (1.2 Å) PDBe PDBsum 1vr7
Catalytic CATH Domains
3.60.90.10 CATHdb (see all for 1vr7)
Click To Show Structure

Enzyme Reaction (EC:4.1.1.50)

S-adenosyl-L-methionine zwitterion
CHEBI:59789ChEBI
+
hydron
CHEBI:15378ChEBI
→
carbon dioxide
CHEBI:16526ChEBI
+
S-adenosylmethioninaminium
CHEBI:57443ChEBI
Alternative enzyme names: S-adenosyl-L-methionine decarboxylase, S-adenosylmethionine decarboxylase, S-adenosyl-L-methionine carboxy-lyase, S-adenosyl-L-methionine carboxy-lyase ((5-deoxy-5-adenosyl)(3-aminopropyl)methylsulfonium-salt-forming),

Enzyme Mechanism

Introduction

Nonhydrolytic serinolysis: Ser63 acts as a nucleophile and attacks the carbonyl of Glu62. The oxyoxazolidine intermediate rearranges into an ester intermediate. His68 removes the C-alpha proton from Ser63 causing beta-elimination to form the C-terminus of the beta-chain and the terminal dehydroalanine residue of the alpha chain. The latter tautomerises into an imine and is hydrolysed to form the terminal pyruvoyl residue of the alpha-chain. AdoMet decarboxylation: the pyruvoyl prosthetic group forms a Schiff base with the alpha-amino group of AdoMet. This prompts the loss of the alpha-carboxylate to form an extended enolate system with the negative charge residing on the amide oxygen of the pyruvoyl group. The carbonyl reforms and the alpha-carbon of the intermediate accepts a proton from Cys83. The Schiff base is then hydrolysed and dcAdoMet is released.

Catalytic Residues Roles

UniProt PDB* (1vr7)
Cys83 Cys83(95)A Cys83 may stabilise the formation of the oxyoxazolidine intermediate in nonhydrolytic serinolysis through a hydrogen bond to the exocyclic oxygen. Cys83 acts a proton donor for the decarboxylated Schiff base during AdoMet decarboxylation. hydrogen bond acceptor, hydrogen bond donor, proton acceptor, polar interaction, proton donor
Glu62 (main-C) Glu62(74)A (main-C) Involved in the autocatalytic serinolysis that results in the formation of the pyruvyl cofactor and C-terminus carboxylate at Glu62. covalently attached, hydrogen bond acceptor, hydrogen bond donor, proton acceptor, electrophile
Ser63 Ser63(75)A Ser63 is the nucleophile for the protocleavage reaction and is subsequently converted to a pyruvoyl residue. It forms a Schiff base with the alpha-amino group of SAM, prompting decarboxylation. The Schiff base is then hydrolysed. covalently attached, hydrogen bond acceptor, hydrogen bond donor, nucleophile, polar interaction, proton donor
His68 His68(80)B His68 removes the C-alpha proton from Ser63 in the ester intermediate during nonhydrolytic serinolysis. This causes beta-elimination and strand cleavage. hydrogen bond acceptor, hydrogen bond donor, proton acceptor, proton donor
Ser55 Ser55(67)B Ser55 is thought to stabilise the oxyoxazolidine intermediate in nonhydrolytic serinolysis by forming a hydrogen bond to the exocyclic oxygen. electrostatic stabiliser
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

intramolecular electrophilic addition, proton transfer, cyclisation, intermediate formation, intramolecular rearrangement, decyclisation, bimolecular elimination, tautomerisation (not keto-enol), bimolecular nucleophilic addition, hydrolysis, intramolecular elimination, deamination, intermediate terminated, native state of cofactor regenerated, inferred reaction step, bimolecular homolytic addition, overall reactant used, enzyme-substrate complex formation, cofactor used, dehydration, schiff base formed, unimolecular elimination by the conjugate base, decarboxylation, enzyme-substrate complex cleavage, overall product formed, native state of enzyme regenerated

References

  1. Ekstrom JL et al. (2001), Biochemistry, 40, 9495-9504. Structure of a human S-adenosylmethionine decarboxylase self-processing ester intermediate and mechanism of putrescine stimulation of processing as revealed by the H243A mutant. DOI:10.2210/pdb1jl0/pdb. PMID:11583148.
  2. Lee BI et al. (2004), J Mol Biol, 340, 1-7. Crystal Structure of the Schiff Base Intermediate Prior to Decarboxylation in the Catalytic Cycle of Aspartate α-Decarboxylase. DOI:10.1016/j.jmb.2004.04.049. PMID:15184017.
  3. Toms AV et al. (2004), J Biol Chem, 279, 33837-33846. Evolutionary Links as Revealed by the Structure of Thermotoga maritima S-Adenosylmethionine Decarboxylase. DOI:10.1074/jbc.m403369200. PMID:15150268.
  4. Xiong H et al. (1999), Biochemistry, 38, 2462-2470. Role of Cysteine-82 in the Catalytic Mechanism of HumanS-Adenosylmethionine Decarboxylase†. DOI:10.1021/bi9825201. PMID:10029540.

Step 1. First step of the non-hydrolytic serinolysis process. The hydroxyl side chain of Ser63 is involved in nucleophilic attack on the main chain carbonyl of Glu62 to form an oxyoxazolidine intermediate.

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Catalytic Residues Roles

Residue Roles
Glu62(74)A (main-C) hydrogen bond acceptor
Ser63(75)A hydrogen bond donor
Ser55(67)B electrostatic stabiliser
Glu62(74)A (main-C) proton acceptor
Ser63(75)A nucleophile
Glu62(74)A (main-C) electrophile
Ser63(75)A proton donor

Chemical Components

ingold: intramolecular electrophilic addition, proton transfer, cyclisation, intermediate formation

Step 2. Part of the non-hydrolytic serinolysis process. The oxyoxazolidine intermediate rearranges to form the ester intermediate.

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Catalytic Residues Roles

Residue Roles
Ser55(67)B electrostatic stabiliser
Glu62(74)A (main-C) hydrogen bond donor, covalently attached
Ser63(75)A hydrogen bond acceptor, covalently attached

Chemical Components

intramolecular rearrangement, proton transfer, decyclisation, intermediate formation

Step 3. Part of the non-hydrolytic serinolysis process. His68 deprotonates the C-alpha of Ser63 causing beta-elimination to form the C-terminus of the beta chain and the terminal dehydroalanine residue of the alpha chain.

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Catalytic Residues Roles

Residue Roles
Ser55(67)B electrostatic stabiliser
Glu62(74)A (main-C) covalently attached
Ser63(75)A hydrogen bond donor
His68(80)B hydrogen bond acceptor, proton acceptor

Chemical Components

ingold: bimolecular elimination, intermediate formation

Step 4. Part of the non-hydrolytic serinolysis process. The dehydroalanine residue tautomerises into an imine.

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Catalytic Residues Roles

Residue Roles
His68(80)B hydrogen bond donor
Ser63(75)A hydrogen bond acceptor

Chemical Components

tautomerisation (not keto-enol), intermediate formation

Step 5. Part of the non-hydrolytic serinolysis process. Water is involved in nucleophilic attack on the imine.

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Catalytic Residues Roles

Residue Roles
His68(80)B hydrogen bond donor
Ser63(75)A hydrogen bond acceptor

Chemical Components

ingold: bimolecular nucleophilic addition, proton transfer, hydrolysis, intermediate formation

Step 6. Final step of the non-hydrolytic serinolysis process. Intramolecular elimination of ammonia to form the pyruvoyl residue.

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Catalytic Residues Roles

Residue Roles
His68(80)B hydrogen bond donor
Ser63(75)A hydrogen bond acceptor, hydrogen bond donor

Chemical Components

ingold: intramolecular elimination, deamination, intermediate terminated, native state of cofactor regenerated

Step 7. First step of Schiff base formation. The amine group is deprotonated by a base, assumed to be ammonia due to lack of further evidence.

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Catalytic Residues Roles

Residue Roles
Ser63(75)A hydrogen bond acceptor

Chemical Components

proton transfer, inferred reaction step

Step 8. Second step of the Schiff base formation. The amine of S-adenosyl-L-methionine is involved in nucleophilic attack on the terminal carbonyl of the pyruvoyl residue.

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Catalytic Residues Roles

Residue Roles
Ser63(75)A hydrogen bond acceptor

Chemical Components

ingold: bimolecular homolytic addition, proton transfer, intermediate formation, overall reactant used, enzyme-substrate complex formation, cofactor used

Step 9. Final step of Schiff base formation. The intermediate dehydrates to form the Schiff base.

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Catalytic Residues Roles

Residue Roles
Ser63(75)A covalently attached

Chemical Components

ingold: intramolecular elimination, dehydration, schiff base formed, intermediate formation

Step 10. The covalently attached intermediate decarboxylates and the post-translationally modified serine acts as an electron sink.

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Catalytic Residues Roles

Residue Roles
Ser63(75)A covalently attached

Chemical Components

ingold: unimolecular elimination by the conjugate base, decarboxylation, intermediate formation

Step 11. Cys83 protonates the intermediate to reform the Schiff base.

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Catalytic Residues Roles

Residue Roles
Cys83(95)A hydrogen bond donor
Ser63(75)A covalently attached, polar interaction
Cys83(95)A proton donor

Chemical Components

proton transfer, schiff base formed, intermediate formation

Step 12. First step one of the hydrolysis of the Schiff base. Water is involved in nucleophilic attack on the imine.

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Catalytic Residues Roles

Residue Roles
Cys83(95)A polar interaction
Ser63(75)A covalently attached, hydrogen bond acceptor

Chemical Components

ingold: bimolecular homolytic addition, proton transfer, hydrolysis, intermediate formation

Step 13. Final step the hydrolysis of the Schiff base. S-Adenosylmethioninamine is eliminated from the intermediate.

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Catalytic Residues Roles

Residue Roles
Ser63(75)A hydrogen bond acceptor, hydrogen bond donor, covalently attached

Chemical Components

ingold: intramolecular elimination, enzyme-substrate complex cleavage, intermediate terminated, overall product formed, native state of cofactor regenerated

Step 14. His68 is deprotonated by a base, assumed to be water based on the lack of other evidence. Cys83 id re-protonated by another base, again assumed to be water.

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Catalytic Residues Roles

Residue Roles
Cys83(95)A hydrogen bond acceptor
His68(80)B hydrogen bond donor
Cys83(95)A proton acceptor
His68(80)B proton donor

Chemical Components

proton transfer, inferred reaction step, native state of enzyme regenerated
Download: Image, Marvin File

Step 1. First step of the non-hydrolytic serinolysis process. The hydroxyl side chain of Ser63 is involved in nucleophilic attack on the main chain carbonyl of Glu62 to form an oxyoxazolidine intermediate.

Step 2. Part of the non-hydrolytic serinolysis process. The oxyoxazolidine intermediate rearranges to form the ester intermediate.

Step 3. Part of the non-hydrolytic serinolysis process. His68 deprotonates the C-alpha of Ser63 causing beta-elimination to form the C-terminus of the beta chain and the terminal dehydroalanine residue of the alpha chain.

Step 4. Part of the non-hydrolytic serinolysis process. The dehydroalanine residue tautomerises into an imine.

Step 5. Part of the non-hydrolytic serinolysis process. Water is involved in nucleophilic attack on the imine.

Step 6. Final step of the non-hydrolytic serinolysis process. Intramolecular elimination of ammonia to form the pyruvoyl residue.

Step 7. First step of Schiff base formation. The amine group is deprotonated by a base, assumed to be ammonia due to lack of further evidence.

Step 8. Second step of the Schiff base formation. The amine of S-adenosyl-L-methionine is involved in nucleophilic attack on the terminal carbonyl of the pyruvoyl residue.

Step 9. Final step of Schiff base formation. The intermediate dehydrates to form the Schiff base.

Step 10. The covalently attached intermediate decarboxylates and the post-translationally modified serine acts as an electron sink.

Step 11. Cys83 protonates the intermediate to reform the Schiff base.

Step 12. First step one of the hydrolysis of the Schiff base. Water is involved in nucleophilic attack on the imine.

Step 13. Final step the hydrolysis of the Schiff base. S-Adenosylmethioninamine is eliminated from the intermediate.

Step 14. His68 is deprotonated by a base, assumed to be water based on the lack of other evidence. Cys83 id re-protonated by another base, again assumed to be water.

Products.

Contributors

Judith A. Reeks, Gemma L. Holliday