HAMAP rule MF_03161

General rule information [?]

Accession	MF_03161
Dates	2-APR-2012 (Created) 19-NOV-2022 (Last updated, Version 17)

Name	Sirtuin_ClassII_euk

Scope

Eukaryota

Template

Q9Y6E7 (SIR4_HUMAN)

case <OC:Eukaryota>

Triggered by

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

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>

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 EC 2.3.1.286 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.

else

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
EC 2.3.1.286

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>

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 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

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