GPMDB0027130OtherMathias RA, et al.InstrumentNot AvailableNot availableHomo_sapiens_viruses, Humanicristea@princeton.edu25525879http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006407http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006418http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006428http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006417http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006427http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006416http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006426http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006415http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006409http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006419http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006408http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006421http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006410http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006420http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006430http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006425http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006414http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006413http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006424http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006412http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006423http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006422http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006411Department of Molecular Biology, Princeton University, et al.Not availableGPMDBSirtuins (SIRTs) are critical enzymes that govern genome regulation, metabolism, and aging. Despite conserved deacetylase domains, mitochondrial SIRT4 and SIRT5 have little to no deacetylase activity, and a robust catalytic activity for SIRT4 has been elusive. Here, we establish SIRT4 as a cellular lipoamidase that regulates the pyruvate dehydrogenase complex (PDH). Importantly, SIRT4 catalytic efficiency for lipoyl- and biotinyl-lysine modifications is superior to its deacetylation activity. PDH, which converts pyruvate to acetyl-CoA, has been known to be primarily regulated by phosphorylation of its E1 component. We determine that SIRT4 enzymatically hydrolyzes the lipoamide cofactors from the E2 component dihydrolipoyllysine acetyltransferase (DLAT), diminishing PDH activity. We demonstrate SIRT4-mediated regulation of DLAT lipoyl levels and PDH activity in cells and in vivo, in mouse liver. Furthermore, metabolic flux switching via glutamine stimulation induces SIRT4 lipoamidase activity to inhibit PDH, highlighting SIRT4 as a guardian of cellular metabolism.Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity.Mathias Rommel A RA,Greco Todd M TM,Oberstein Adam A,Budayeva Hanna G HG,Chakrabarti Rumela R,Rowland Elizabeth A EA,Kang Yibin Y,Shenk Thomas T,Cristea Ileana M IM,Mathias Rommel A RA, Greco Todd M TM, Oberstein Adam A, Budayeva Hanna G HG, Chakrabarti Rumela R, Rowland Elizabeth A EA, Kang Yibin Y, Shenk Thomas T, Cristea Ileana M IMpyruvate dehydrogenase (lipoamide) activity, pyruvate:lipoamide 2-oxidoreductase (decarboxylating and acceptor-acetylating) activity, MtPDC (mitochondrial pyruvate dehydogenase complex) activity, PDH, acceptor-acetylating)., pyruvate dehydrogenase complex activity, pyruvate:dihydrolipoyllysine-residue acetyltransferase-lipoyllysine 2-oxidoreductase (decarboxylatingMtPDC (mitochondrial pyruvate dehydogenase complex) activity, data, Lysine Hydrochloride, GLM2, 2-oxopropanoate, Pyruvic, SIR2L4, Phosphorylations, pyruvate dehydrogenase complex (lipoamide), 8-thioctic amide, pyranose-quinone oxidoreductase activity, PDCE2, Cell, phosphorylation, Productivity, dihydrolipoyl dehydrogenase complex, MHAM, mito, Lysine Acetate, Experiment, pyruvate dehydrogenase complex activity, PTEN1, lipoamide, PDC-E2, Acetate, CWS1, 1, 2, (+-)-isomer, 4930596O17Rik, TEP1, Lysine, deacetylation, 6, L-Lysine, acceptor-acetylating), L Lysine, quinone-dependent pyranose dehydrogenase activity., Acid, Dehydrogenase Complex, 10q23del, PDHC, cell, MMAC1, Complex, alpha-lipoic amide, epsilon-diaminocaproic acid, 2-dithiolane-3-valeramide, PDH, DLTA, Pyruvate dehydrogenase complex deficiency, pyranose:acceptor oxidoreductase activity, alpha, Pyruvate Dehydrogenase, pyruvate:dihydrolipoyllysine-residue acetyltransferase-lipoyllysine 2-oxidoreductase (decarboxylating, C6H14N2O2, lipamide, quinone-dependent pyranose dehydrogenase activity, pyruvate:lipoamide 2-oxidoreductase (decarboxylating and acceptor-acetylating) activity, DEC, Pyruvate, Lysin, pyruvate, pyruvate dehydrogenase (lipoamide) activity, pyranose dehydrogenase activity, 6332404G05Rik, 6-diaminohexanoic acid, BZS, Enisylpyruvate dehydrogenase (lipoamide) activity, pyruvate:lipoamide 2-oxidoreductase (decarboxylating and acceptor-acetylating) activity, MtPDC (mitochondrial pyruvate dehydogenase complex) activity, PDH, acceptor-acetylating)., pyruvate dehydrogenase complex activity, pyruvate:dihydrolipoyllysine-residue acetyltransferase-lipoyllysine 2-oxidoreductase (decarboxylatingbiochemical pathways, 1500032M05Rik, 3.4.22.-, GLUTAMINE, Metabolic Process, Lysine Hydrochloride, Laboratory, Biocatalysts, Processes, 5-diamino-5-oxopentanoic acid, Mus domesticus, 10)/f/h9H, Metabolic Concepts, InChIKey=ZDXPYRJPNDTMRX-HDAMEQSMCZ, SIR2L4, (H2, SIR2L5, AV001953, pyruvate dehydrogenase complex (lipoamide), C5H10N2O3, Levoglutamide, 8-thioctic amide, mini-ICE, CASP-14, Aging, Metabolic Processes, (2S)-2-amino-4-carbamoylbutanoic acid, PDCE2, House Mouse, phosphorylation, L-(+)-glutamine, Productivity, jecur, dihydrolipoyl dehydrogenase complex, Glutaminsaeure-5-amid, Lysine Acetate, L-glutamine, L-Glutaminsaeure-5-amid, PDC-E2, House, Biological, Metabolism, AGING BIOL, Concepts, 1, Mus musculus domesticus, 2, L-2-aminoglutaramic acid, Lysine, deacetylation, 6, 2-Aminoglutaramic acid, Metabolism Concept, 7, Phenomenon, 9, Metabolism Phenomena, Mice, L Lysine, Senescence, Dehydrogenase Complex, enzymes, Genomes, catabolism, 0610012J09Rik, Swiss, (2S)-2, Complex, D-Glutamine, Q, epsilon-diaminocaproic acid, iecur, Metabolic Concept, Swiss Mice, metabolic process resulting in cell growth, pyranose:acceptor oxidoreductase activity, pyruvate:dihydrolipoyllysine-residue acetyltransferase-lipoyllysine 2-oxidoreductase (decarboxylating, C6H14N2O2, "mouse" EXACT common_name [], lipamide, quinone-dependent pyranose dehydrogenase activity, pyruvate:lipoamide 2-oxidoreductase (decarboxylating and acceptor-acetylating) activity, "Mus muscaris" RELATED misnomer [], 7H2, Biological Aging, Lysin, biotransformation, intermediary metabolism., 6332404G05Rik, "mice C57BL/6xCBA/CaJ hybrid" RELATED misspelling [], L-Glutamine, house mouse, Catabolism, Glutamin, incorporation, MtPDC (mitochondrial pyruvate dehydogenase complex) activity, degradation, Process, 2-oxopropanoate, Sir2 like Proteins, Pyruvic, Entire liver, metabolism resulting in cell growth, mouse, Phosphorylations, enzyme activity, pyranose-quinone oxidoreductase activity, 1-2, L-2-Aminoglutaramic acid, Cell, mice C57BL/6xCBA/CaJ hybrid, Mus muscaris, Concept, Metabolic Phenomena, 6H2, Metabolism Concepts, Sir2-like Proteins, InChI=1/C5H10N2O3/c6-3(5(9)10)1-2-4(7)8/h3H, pyruvate dehydrogenase complex activity, lipoamide, Mus, Acetate, Mini-ICE, Phenomena, Glutamic acid 5-amide, Silent Mating Type Information Regulator 2 like Proteins, (+-)-isomer, NC(CCC(N)=O)C(O)=O, 4930596O17Rik, L-Glutamin, BIOL AGING, metabolism, L-Lysine, acceptor-acetylating), Metabolic Phenomenon, L Glutamine, Acid, Mus musculus, Hgln, mobilization, multicellular organism metabolic process, biodegradation, Caspase-14 subunit p10, Metabolic, PDHC, Glutamic acid amide, 8)(H, lipoyl-X-hydrolase, mice, alpha-lipoic amide, Swiss Mouse, 2-dithiolane-3-valeramide, PDH, DLTA, House Mice, Pyruvate dehydrogenase complex deficiency, Caspase-14 subunit p19, whole genome, alpha, Pyruvate Dehydrogenase, (S)-2, MICE, turnover, Laboratory Mice, domesticus, L-glutamic acid gamma-amide, "house mouse" EXACT genbank_common_name [], Silent Mating Type Information Regulator 2-like Proteins, ageing, Livers, 2-amino-4-carbamoylbutanoic acid, single-organism metabolic process, Pyruvate, D Glutamine, pyruvate, glutamic acid gamma-amide, pyruvate dehydrogenase (lipoamide) activity, pyranose dehydrogenase activity, regulation, Mouse, cellular metabolism, 6-diaminohexanoic acid, Enisyl, Laboratory Mouse, Anabolism270130http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320006423dbgap_ncbi~0patentfamilies~0rfam~0uniprot~4merops~0complex-portal~0wormbaseparasite~0embl-covid19~0reactome~0emdb~0wgs_masters~0ebiweb_resources~0opentargets_genetics~0biomodels_all~0ipd-mhc~0ebiweb_teams~0taxonomy~0genome_assembly~0sc-experiments~0ebiweb_people~0enzymeportal_enzymes~0intact~106ipd-nhkir~0cellosaurus~0pdbe~0chebi~0patentproteins~0interpro7~0uniref~0pdbekb~2chembl~0gpcrdb~0hgnc~0sc-genes~0ebiweb_training~0alphafold~0imgt-hla~0patentnucleotides~0ensemblroot~0eva_studies~0rhea~8non-coding~0europepmc~0pubmed~1identifiers_registry~0pdbechem~0hpa-covid19~0eva-variants-covid19~0biosamples~0gwas_catalog~0biotools~0tls_masters~0mesh~0coding~0sra~0opentargets~0efo~0embl-pathogen~0project~0pride~1human_diseases~0geo_datasets~0embl~0treefam~0uniparc~0ols~0dgva~0intenz~0tsa_masters~0biosamples-covid19~0ebiweb_corporate~0omim~0go~5lrg~0earlycause-molecular-sequences~0ipd-kir~0empiar~0rnacentral~0orcid_data_claims~0gpmdb~2lineage-covid19~0metagenomics~0pfam~0pride archive~1varsite~00Resource Reanalysis0.00.00.0083281924737816161.00.0falseSirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity.Data from ProteomeXchange, PXD ID: PXD001447. Experiment: SIRT4_MITO_MOCK1, file: SIRT4_MITO_MOCK1_05.mzml. Published as part of Cell. 2014 Dec 18;159(7):1615-25 . From the Abstract: {{i}} ... Here, we establish SIRT4 as a cellular lipoamidase that regulates the pyruvate dehydrogenase complex (PDH). Importantly, SIRT4 catalytic efficiency for lipoyl- and biotinyl-lysine modifications is superior to its deacetylation activity. PDH, which converts pyruvate to acetyl-CoA, has been known to be primarily regulated by phosphorylation of its E1 component. We determine that SIRT4 enzymatically hydrolyzes the lipoamide cofactors from the E2 component dihydrolipoyllysine acetyltransferase (DLAT), diminishing PDH activity ... {{/i}}2015-01-06GPM3232000642325525879PXD001447PXD001447