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HAMAP rule MF_03161

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General rule information [?]

Accession MF_03161
Dates 2-APR-2012 (Created)
19-NOV-2022 (Last updated, Version 17)
Name Sirtuin_ClassII_euk
Template Q9Y6E7 (SIR4_HUMAN)
case <OC:Eukaryota>
end case

Propagated annotation [?]

Identifier, protein and gene names [?]

case <OC:Mammalia>
Protein name
RecName: Full=NAD-dependent protein lipoamidase sirtuin-4, mitochondrial;
EC 2.3.1.-;
AltName: Full=NAD-dependent ADP-ribosyltransferase sirtuin-4;
EC 2.4.2.-;
AltName: Full=NAD-dependent protein biotinylase sirtuin-4;
EC 2.3.1.-;
AltName: Full=NAD-dependent protein deacetylase sirtuin-4;
AltName: Full=Regulatory protein SIR2 homolog 4;
AltName: Full=SIR2-like protein 4;
Flags: Precursor;
Gene name
Protein name
RecName: Full=NAD-dependent protein deacylase;
EC 2.3.1.-;
AltName: Full=Regulatory protein SIR2 homolog;
end case

Comments [?]

case <OC:Mammalia>
Function Acts as NAD-dependent protein lipoamidase, biotinylase, deacetylase and ADP-ribosyl transferase. Catalyzes more efficiently removal of lipoyl- and biotinyl- than acetyl-lysine modifications. Inhibits the pyruvate dehydrogenase complex (PDH) activity via the enzymatic hydrolysis of the lipoamide cofactor from the E2 component, DLAT, in a phosphorylation-independent manner. Catalyzes the transfer of ADP-ribosyl groups onto target proteins, including mitochondrial GLUD1, inhibiting GLUD1 enzyme activity. Acts as a negative regulator of mitochondrial glutamine metabolism by mediating mono ADP-ribosylation of GLUD1: expressed in response to DNA damage and negatively regulates anaplerosis by inhibiting GLUD1, leading to block metabolism of glutamine into tricarboxylic acid cycle and promoting cell cycle arrest. In response to mTORC1 signal, SIRT4 expression is repressed, promoting anaplerosis and cell proliferation. Acts as a tumor suppressor. Also acts as a NAD-dependent protein deacetylase: mediates deacetylation of 'Lys-471' of MLYCD, inhibiting its activity, thereby acting as a regulator of lipid homeostasis. Does not seem to deacetylate PC. Controls fatty acid oxidation by inhibiting PPARA transcriptional activation. Impairs SIRT1-PPARA interaction probably through the regulation of NAD(+) levels. Down-regulates insulin secretion.
Catalytic activity RHEA:56612: L-cysteinyl-[protein] + NAD(+) = H(+) + nicotinamide + S-(ADP-D-ribosyl)-L-cysteinyl-[protein]
RHEA:63640: (R)-N(6)-lipoyl-L-lysyl-[protein] + H2O + NAD(+) = 2''-O-lipoyl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide
PhysiologicalDirection=left-to-right (RHEA:63641)
RHEA:70479: H2O + N(6)-biotinyl-L-lysyl-[protein] + NAD(+) = 2''-O-biotinyl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide
PhysiologicalDirection=left-to-right (RHEA:70480)
RHEA:43636: H2O + N(6)-acetyl-L-lysyl-[protein] + NAD(+) = 2''-O-acetyl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide
PhysiologicalDirection=left-to-right (RHEA:43637)
Subunit Interacts with GLUD1, IDE and SLC25A5. Interacts with DLAT and PDHX.
Miscellaneous According to some authors, ADP-ribosyltransferase activity of sirtuins may be an inefficient side reaction of the deacetylase activity and may not be physiologically relevant.
Function NAD-dependent protein deacylase. Catalyzes the NAD-dependent hydrolysis of acyl groups from lysine residues.
end case
Catalytic activity RHEA:43636: H2O + N(6)-acetyl-L-lysyl-[protein] + NAD(+) = 2''-O-acetyl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide
case <FTGroup:1>
Cofactor Zn(2+)
Note: Binds 1 zinc ion per subunit.
end case
Subcellular location Mitochondrion matrix.
case not <OC:Mammalia> and not <AnyFeature:TransitM>
Miscellaneous This protein may be expected to contain an N-terminal transit peptide but none has been predicted.
end case
Similarity Belongs to the sirtuin family. Class II subfamily.

Keywords [?]

case <OC:Mammalia>
end case
case <FTGroup:1>
end case

Gene Ontology [?]

GO:0005759; Cellular component: mitochondrial matrix.
GO:0034979; Molecular function: NAD-dependent protein deacetylase activity.
case <OC:Mammalia>
GO:0003950; Molecular function: NAD+ ADP-ribosyltransferase activity.
end case
GO:0070403; Molecular function: NAD+ binding.
GO:0006476; Biological process: protein deacetylation.
case <FTGroup:1>
GO:0008270; Molecular function: zinc ion binding.
end case

Cross-references [?]

PROSITE PS50305; SIRTUIN; 1; trigger=PRU00236;
Pfam PF02146; SIR2; 1;

Computed features [?]

case not <OC:Mammalia>
General TransitM; -; 0-1; trigger=yes;
end case

Features [?]

case <OC:Mammalia>
From: SIR4_HUMAN (Q9Y6E7)
Key     From     To       Description   Tag   Condition   FTGroup
TRANSIT     Nter     28       Mitochondrion        
CHAIN     29     Cter              
end case
BINDING     62     82       /ligand="NAD(+)" /ligand_id="ChEBI:CHEBI:57540     G-A-G-x-S-T-x-x-G-[IV]-P-D-Y-R-x(7)  
BINDING     143     146       /ligand="NAD(+)" /ligand_id="ChEBI:CHEBI:57540     Q-N-V-D  
BINDING     260     262       /ligand="NAD(+)" /ligand_id="ChEBI:CHEBI:57540     G-[ST]-S  
BINDING     286     288       /ligand="NAD(+)" /ligand_id="ChEBI:CHEBI:57540     N-x-G  
ACT_SITE     161     161       Proton acceptor     H  
BINDING     169     169       /ligand="Zn(2+)" /ligand_id="ChEBI:CHEBI:29105     C   1
BINDING     172     172       /ligand="Zn(2+)" /ligand_id="ChEBI:CHEBI:29105     C   1
BINDING     220     220       /ligand="Zn(2+)" /ligand_id="ChEBI:CHEBI:29105     C   1
BINDING     223     223       /ligand="Zn(2+)" /ligand_id="ChEBI:CHEBI:29105     C   1
BINDING     304     304       /ligand="NAD(+)" /ligand_id="ChEBI:CHEBI:57540        

Additional information [?]

Size range 273-373 amino acids
Related rules None
Fusion None