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HAMAP rule MF_03161

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General rule information [?]

Accession MF_03161
Dates 2-APR-2012 (Created)
3-SEP-2024 (Last updated, Version 20)
Name Sirtuin_ClassII_euk
Scope(s) Eukaryota
Template(s) Q9Y6E7 (SIR4_HUMAN); [ Recover all ]
Triggered by
case c? <OC:Eukaryota>
HAMAP; MF_01967 (Get profile general information and statistics)
end case

Propagated annotation [?]

Identifier, protein and gene names [?]

Identifier SIR4
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;
                 EC=2.3.1.286;
AltName: Full=Regulatory protein SIR2 homolog 4;
AltName: Full=SIR2-like protein 4;
                 Flags: Precursor;
Gene name Name=SIRT4;
else
Protein name RecName: Full=NAD-dependent protein deacylase;
                 EC=2.3.1.-;
AltName: Full=Regulatory protein SIR2 homolog;
end case

Comments [?]

case <OC:Mammalia>
FUNCTIONActs 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 Reaction=L-cysteinyl-[protein] + NAD(+) = S-(ADP-D-ribosyl)-L- cysteinyl-[protein] + nicotinamide + H(+); Xref=Rhea:RHEA:56612, Rhea:RHEA- COMP:10131, Rhea:RHEA-COMP:14624, ChEBI:CHEBI:15378, ChEBI:CHEBI:17154, ChEBI:CHEBI:29950, ChEBI:CHEBI:57540, ChEBI:CHEBI:140607;
CATALYTIC ACTIVITY Reaction=N(6)-[(R)-lipoyl]-L-lysyl-[protein] + NAD(+) + H2O = 2''-O- lipoyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein]; Xref=Rhea:RHEA:63640, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:10474, ChEBI:CHEBI:15377, ChEBI:CHEBI:17154, ChEBI:CHEBI:29969, ChEBI:CHEBI:57540, ChEBI:CHEBI:83099, ChEBI:CHEBI:189572;
CATALYTIC ACTIVITY Reaction=N(6)-biotinyl-L-lysyl-[protein] + NAD(+) + H2O = 2''-O- biotinyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein]; Xref=Rhea:RHEA:70479, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:10505, ChEBI:CHEBI:15377, ChEBI:CHEBI:17154, ChEBI:CHEBI:29969, ChEBI:CHEBI:57540, ChEBI:CHEBI:83144, ChEBI:CHEBI:189573; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70480;
CATALYTIC ACTIVITY Reaction=N(6)-acetyl-L-lysyl-[protein] + NAD(+) + H2O = 2''-O-acetyl- ADP-D-ribose + nicotinamide + L-lysyl-[protein]; Xref=Rhea:RHEA:43636, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:10731, ChEBI:CHEBI:15377, ChEBI:CHEBI:17154, ChEBI:CHEBI:29969, ChEBI:CHEBI:57540, ChEBI:CHEBI:61930, ChEBI:CHEBI:83767; EC=2.3.1.286; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:43637;
SUBUNITInteracts with GLUD1, IDE and SLC25A5. Interacts with DLAT and PDHX.
MISCELLANEOUSAccording to some authors, ADP-ribosyltransferase activity of sirtuins may be an inefficient side reaction of the deacetylase activity and may not be physiologically relevant.
else
FUNCTIONNAD-dependent protein deacylase. Catalyzes the NAD-dependent hydrolysis of acyl groups from lysine residues.
end case
CATALYTIC ACTIVITY Reaction=N(6)-acetyl-L-lysyl-[protein] + NAD(+) + H2O = 2''-O-acetyl- ADP-D-ribose + nicotinamide + L-lysyl-[protein]; Xref=Rhea:RHEA:43636, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:10731, ChEBI:CHEBI:15377, ChEBI:CHEBI:17154, ChEBI:CHEBI:29969, ChEBI:CHEBI:57540, ChEBI:CHEBI:61930, ChEBI:CHEBI:83767; EC=2.3.1.286;
case <FTGroup:1>
COFACTOR Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Note=Binds 1 zinc ion per subunit.;
end case
SUBCELLULAR LOCATIONMitochondrion matrix.
case not <OC:Mammalia> and not <AnyFeature:TransitM>
MISCELLANEOUSThis protein may be expected to contain an N-terminal transit peptide but none has been predicted.
end case
SIMILARITYBelongs to the sirtuin family. Class II subfamily.

Keywords [?]

case <OC:Mammalia>
Transit peptide
end case
Metal-binding
Mitochondrion
NAD
case <FTGroup:1>
Metal-binding
Zinc
end case
Transferase

Gene Ontology [?]

GO:0005759; Cellular component:mitochondrial matrix
GO:0034979; Molecular function:NAD-dependent protein lysine deacetylase activity
case <OCellular component:Mammalia>
GO:0003950; Molecular function:NAD+-protein poly-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;
Pfam PF02146; SIR2; 1;
General TransitM; -; 0-1;

Features [?]

From: SIR4_HUMAN (Q9Y6E7)
Key From To Description Tag Condition FTGroup
case <OC:Mammalia>
TRANSIT Nter 28 /note="Mitochondrion"
CHAIN 29 Cter /note=""
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 /note="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 Nter: None Cter: None



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