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FLASH GENE
Symbol SIRT4 contributors: mct - updated : 05-05-2020
HGNC name sirtuin (silent mating type information regulation 2 homolog) 4 (S. cerevisiae)
HGNC id 14932
DNA
TYPE functioning gene
STRUCTURE 10.92 kb     4 Exon(s)
10 Kb 5' upstream gene genomic sequence study
MAPPING cloned Y linked N status provisional
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
4 - 1213 35.06 314 - 2006 16959573
EXPRESSION
Type restricted
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Cardiovascularheart   highly Homo sapiens
Digestiveliver   highly Homo sapiens
Endocrinepancreasislet of Langerhans    Homo sapiens
Nervousbrain   highly Homo sapiens
Urinarykidney   highly Homo sapiens
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Muscularstriatumskeletal moderately Homo sapiens
cells
SystemCellPubmedSpeciesStageRna symbol
Endocrineislet cell (alpha,beta...) Homo sapiens
Nervousneuron Homo sapiens
cell lineage
cell lines
fluid/secretion
at STAGE
physiological period fetal
Text tissues
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a deacetylase sirtuin-type core domain
  • mono polymer complex
    HOMOLOGY
    interspecies homolog to yeast Sir2
    homolog to E.coli CobB
    ortholog to rattus Sirt4 predicted
    ortholog to murine Sirt4
    homolog to Drosophila sirt4
    Homologene
    FAMILY
  • sirtuin family
  • CATEGORY enzyme , regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,inner
    intracellular,cytoplasm,organelle,mitochondria,matrix
    intracellular,cytoplasm,organelle,membrane
    text
  • matrix protein and becomes cleaved at amino acid 28 after import into mitochondria
  • mainly localized in the mitochondria
  • SIRT4 is localized to mitochondria within the brain
  • basic FUNCTION
  • by participating in the stress response to genomic insults, sirtuins are thought to protect against cancer, but they are also emerging as direct participants in the growth of some cancers
  • playing a role in the regulation of insulin secretion
  • lacks deacetylase activities but efficiently works as an ADP-ribosyltransferase
  • play a central role in epigenetic gene silencing, DNA repair and recombination, cell-cycle, microtubule organization, and in the regulation of aging
  • required to maintain cell survival after genotoxic stress in a NAD+-dependent manner
  • with SIRT3, modulate mitochondrial function in response to its [NADH]/[NAD+] ratio by regulating the activity of key metabolic enzymes
  • implicated in the regulation of insulin secretion by modulation of glutamate dehydrogenase
  • playing a role in regulating hepatic fat metabolism
  • is potentially a negative regulator of fat oxidation and overall mitochondrial oxidative metabolism
  • negative regulator of oxidative metabolism, which is in stark contrast to the functions of SIRT1 and SIRT3, which enhance the oxidative capacity of tissues
  • connected to keratinocyte differentiation, chronological aging, ultraviolet radiation (UVR) response, alopecia, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)
  • SIRT4 and GLUD1 overexpression play antagonistic roles in regulating gliogenesis
  • SIRT4 is an important regulator of lipid homeostasis
  • SIRT4 is a guardian of cellular metabolism
  • is a crucial regulator of the stress resistance of cancer cells
  • essential roles in stress resistance and may be an important therapeutic target for cancer treatment
  • SIRT4 is a crucial player maintaining insulin secretion and glucose homeostasis during aging
  • stress-responsive mitochondrial sirtuin SIRT4 controls cellular energy metabolism in a NAD+-dependent manner and is implicated in cellular senescence and aging
  • modulates energy homeostasis in multiple cell types and tissues
  • critical role for SIRT4 in the control of energy metabolism and meiotic apparatus during oocyte maturation and SIRT4 is an essential factor determining oocyte quality
  • in mitochondrial sirtuins, SIRT4 was the last of less well-understood mitochondrial sirtuins especially for its robust enzymatic activity
  • having robust deacylase activity in addition to the already accepted substrate-dependent lipoamidase and deacetylase properties
  • is proposed as either a mitochondrial tumor suppressor or a tumor-promoting protein in a context-dependent manner
  • CELLULAR PROCESS nucleotide, transcription, regulation
    protein, post translation
    PHYSIOLOGICAL PROCESS
    text chromatin silencing, protein ADP-ribosylation
    PATHWAY
    metabolism
    signaling
    a component
  • chromatin silencing complex
  • INTERACTION
    DNA binding
    RNA
    small molecule metal binding, cofactor,
  • Zn2+
  • NAD
  • protein
  • downregulating GLUD1
  • MLYCD is a SIRT4 target
  • SIRT4 regulates mitochondrial ATP homeostasis
  • ability of SIRT4 to regulate ATP levels via SLC25A5 and a feedback loop involving AMPK
  • is a cellular lipoamidase that regulates the pyruvate dehydrogenase complex (PDH)
  • CTBP1 have an essential role in promoting glutaminolysis by directly repressing the expression of SIRT4, a repressor of glutaminolysis by enzymatically modifying glutamate dehydrogenase in mitochondria, in cancer cells
  • SIRT4 interacts physically with OPA1, and SIRT4-OPA1 axis is causally linked to mitochondrial dysfunction and altered mitochondrial dynamics that translates into aging-associated decreased mitophagy based on an unbalanced mitochondrial fusion/fission cycle
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
             
    loss of SIRT4 in insulinoma cells activates GLUD1, thereby upregulating amino acid-stimulated insulin secretion
    tumoral     --low  
    in hepatocellular carcinoma tumour tissues, and the expression of SIRT4 in peritumour tissues was positively associated with survival in patients
    constitutional     --over  
    Protein levels of SIRT 4 were significantly higher in HUVECs from HELLP compared to control after 60 and 120 minutes of hypoxia
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    diabetetype 2 
    its inhibition increases fat oxidative capacity in liver and mitochondrial function in muscle, which might provide therapeutic benefits for diseases associated with ectopic lipid storage such as type 2 diabetes
    cancerdigestivecolon
    may serve as a novel therapeutic target in colorectal cancer
    ANIMAL & CELL MODELS
  • mouse oocytes overexpressing Sirt4 are unable to completely progress through meiosis, showing the inadequate mitochondrial redistribution, lowered ATP content, elevated reactive oxygen species (ROS) level, with the severely disrupted spindle/chromosome organization