Abstract
Sirtuins are recently redefined as a family of nicotinamide adenine dinucleotide
(NAD)-dependent deacylases. Sirtuins in mammals including human have
seven members, which are SIRT1-7. Compared to other sirtuin members, not
much study is focused on mitochondrial sirtuins (SIRT3-5). In mitochondrial sirtuins, SIRT4 was the last of less well-understood mitochondrial sirtuins especially for its robust enzymatic activity.
This makes SIRT4 become the last puzzle of mitochondrial sirtuins, and
thus brings some obstacles for studying SIRT4 biological functions or
developing SIRT4 modulators.
In this review, we will summarize and discuss the current findings for
substrates, biological functions and possible enzymatic activities of
SIRT4. The purpose of this review is to facilitate in discovering the
robust enzymatic activity of SIRT4 and eventually finish this last
puzzle of mitochondrial sirtuins.
Protein
NAD-dependent protein lipoamidase sirtuin-4, mitochondrial
Gene SIRT4
Function
Acts
as NAD-dependent protein lipoamidase, ADP-ribosyl transferase and
deacetylase. 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 (PubMed:25525879).
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 (PubMed:16959573, PubMed:17715127).
In response to mTORC1 signal, SIRT4 expression is repressed, promoting
anaplerosis and cell proliferation. Acts as a tumor suppressor (PubMed:23562301, PubMed:23663782).
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 (By similarity). Does not
seem to deacetylate PC (PubMed:23438705).
Controls fatty acid oxidation by inhibiting PPARA transcriptional
activation. Impairs SIRT1:PPARA interaction probably through the
regulation of NAD+ levels (PubMed:24043310). Down-regulates insulin secretion. UniRule annotation 7 Publications
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