PCKGC_BOVIN
ID PCKGC_BOVIN Reviewed; 622 AA.
AC Q8HYZ4;
DT 25-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 111.
DE RecName: Full=Phosphoenolpyruvate carboxykinase, cytosolic [GTP] {ECO:0000305};
DE Short=PEPCK-C;
DE EC=4.1.1.32 {ECO:0000250|UniProtKB:P35558};
DE AltName: Full=Serine-protein kinase PCK1 {ECO:0000305};
DE EC=2.7.11.- {ECO:0000250|UniProtKB:P35558};
GN Name=PCK1 {ECO:0000250|UniProtKB:P35558}; Synonyms=PPCK1;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=12388798; DOI=10.1152/physiolgenomics.00108.2001;
RA Agca C., Greenfield R.B., Hartwell J.R., Donkin S.S.;
RT "Cloning and characterization of bovine cytosolic and mitochondrial PEPCK
RT during transition to lactation.";
RL Physiol. Genomics 11:53-63(2002).
RN [2]
RP INDUCTION.
RX PubMed=2213709;
RA McGrane M.M., Yun J.S., Roesler W.J., Park E.A., Wagner T.E., Hanson R.W.;
RT "Developmental regulation and tissue-specific expression of a chimaeric
RT phosphoenolpyruvate carboxykinase/bovine growth hormone gene in transgenic
RT animals.";
RL J. Reprod. Fertil. Suppl. 41:17-23(1990).
CC -!- FUNCTION: Cytosolic phosphoenolpyruvate carboxykinase that catalyzes
CC the reversible decarboxylation and phosphorylation of oxaloacetate
CC (OAA) and acts as the rate-limiting enzyme in gluconeogenesis.
CC Regulates cataplerosis and anaplerosis, the processes that control the
CC levels of metabolic intermediates in the citric acid cycle. At low
CC glucose levels, it catalyzes the cataplerotic conversion of
CC oxaloacetate to phosphoenolpyruvate (PEP), the rate-limiting step in
CC the metabolic pathway that produces glucose from lactate and other
CC precursors derived from the citric acid cycle. At high glucose levels,
CC it catalyzes the anaplerotic conversion of phosphoenolpyruvate to
CC oxaloacetate (By similarity). Acts as a regulator of formation and
CC maintenance of memory CD8(+) T-cells: up-regulated in these cells,
CC where it generates phosphoenolpyruvate, via gluconeogenesis. The
CC resultant phosphoenolpyruvate flows to glycogen and pentose phosphate
CC pathway, which is essential for memory CD8(+) T-cells homeostasis (By
CC similarity). In addition to the phosphoenolpyruvate carboxykinase
CC activity, also acts as a protein kinase when phosphorylated at Ser-90:
CC phosphorylation at Ser-90 by AKT1 reduces the binding affinity to
CC oxaloacetate and promotes an atypical serine protein kinase activity
CC using GTP as donor. The protein kinase activity regulates lipogenesis:
CC upon phosphorylation at Ser-90, translocates to the endoplasmic
CC reticulum and catalyzes phosphorylation of INSIG proteins (INSIG1 and
CC INSIG2), thereby disrupting the interaction between INSIG proteins and
CC SCAP and promoting nuclear translocation of SREBP proteins
CC (SREBF1/SREBP1 or SREBF2/SREBP2) and subsequent transcription of
CC downstream lipogenesis-related genes (By similarity).
CC {ECO:0000250|UniProtKB:P35558, ECO:0000250|UniProtKB:Q9Z2V4}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=GTP + oxaloacetate = CO2 + GDP + phosphoenolpyruvate;
CC Xref=Rhea:RHEA:10388, ChEBI:CHEBI:16452, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:37565, ChEBI:CHEBI:58189, ChEBI:CHEBI:58702; EC=4.1.1.32;
CC Evidence={ECO:0000250|UniProtKB:P35558};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10389;
CC Evidence={ECO:0000250|UniProtKB:P35558};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:10390;
CC Evidence={ECO:0000250|UniProtKB:P35558};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=GTP + L-seryl-[protein] = GDP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:64020, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:37565,
CC ChEBI:CHEBI:58189, ChEBI:CHEBI:83421;
CC Evidence={ECO:0000250|UniProtKB:P35558};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64021;
CC Evidence={ECO:0000250|UniProtKB:P35558};
CC -!- COFACTOR:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000250|UniProtKB:P35558};
CC Note=Binds 1 Mn(2+) ion per subunit. {ECO:0000250|UniProtKB:P35558};
CC -!- ACTIVITY REGULATION: Phosphoenolpyruvate carboxykinase activity is
CC regulated by acetylation and glucose levels (By similarity). The
CC anaplerotic conversion of phosphoenolpyruvate to oxaloacetate is
CC improved by PCK1 acetylation on Lys-91 (K91ac), Lys-473 (K473ac) and
CC Lys-521 (K521ac) (By similarity). High glucose concentrations favor
CC PCK1 anaplerotic activity by triggering acetylation on Lys-91 (K91ac).
CC At low glucose levels, SIRT1-mediated deacetylation of Lys-91 promotes
CC the cataplerotic conversion of oxaloacetate to phosphoenolpyruvate.
CC Phosphorylation at Ser-90 reduces the binding affinity to oxaloacetate
CC and converts the enzyme into an atypical protein kinase using GTP as
CC donor (By similarity). {ECO:0000250|UniProtKB:P07379,
CC ECO:0000250|UniProtKB:P35558}.
CC -!- PATHWAY: Carbohydrate biosynthesis; gluconeogenesis.
CC {ECO:0000250|UniProtKB:P35558}.
CC -!- SUBUNIT: Monomer. {ECO:0000250|UniProtKB:P35558}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:P35558}. Endoplasmic reticulum
CC {ECO:0000250|UniProtKB:P35558}. Note=Phosphorylation at Ser-90 promotes
CC translocation to the endoplasmic reticulum.
CC {ECO:0000250|UniProtKB:P35558}.
CC -!- INDUCTION: Regulated by insulin, cAMP and dexamethasone.
CC {ECO:0000269|PubMed:2213709}.
CC -!- PTM: Acetylated. Lysine acetylation by p300/EP300 is increased on high
CC glucose conditions. Lysine acetylation promotes ubiquitination by UBR5.
CC Acetylation is enhanced in the presence of BAG6. Deacetylated by SIRT2.
CC Deacetylation of Lys-91 is carried out by SIRT1 and depends on PCK1
CC phosphorylation levels. {ECO:0000250|UniProtKB:P35558}.
CC -!- PTM: Phosphorylated in a GSK3B-mediated pathway; phosphorylation
CC affects the efficiency of SIRT1-mediated deacetylation, and regulates
CC PCK1 ubiquitination and degradation. Phosphorylation at Ser-90 by AKT1
CC reduces the binding affinity to oxaloacetate and promotes the protein
CC kinase activity: phosphorylated PCK1 translocates to the endoplasmic
CC reticulum, where it phosphorylates INSIG1 and INSIG2.
CC {ECO:0000250|UniProtKB:P35558}.
CC -!- PTM: Ubiquitination by UBR5 leads to proteasomal degradation.
CC {ECO:0000250|UniProtKB:P35558}.
CC -!- MISCELLANEOUS: In eukaryotes there are two isozymes: a cytoplasmic one
CC and a mitochondrial one. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the phosphoenolpyruvate carboxykinase [GTP]
CC family. {ECO:0000305}.
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DR EMBL; AY145503; AAN61102.1; -; mRNA.
DR RefSeq; NP_777162.1; NM_174737.2.
DR AlphaFoldDB; Q8HYZ4; -.
DR SMR; Q8HYZ4; -.
DR STRING; 9913.ENSBTAP00000002520; -.
DR PaxDb; Q8HYZ4; -.
DR PeptideAtlas; Q8HYZ4; -.
DR PRIDE; Q8HYZ4; -.
DR GeneID; 282855; -.
DR KEGG; bta:282855; -.
DR CTD; 5105; -.
DR eggNOG; KOG3749; Eukaryota.
DR InParanoid; Q8HYZ4; -.
DR OrthoDB; 286671at2759; -.
DR UniPathway; UPA00138; -.
DR Proteomes; UP000009136; Unplaced.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0030145; F:manganese ion binding; IBA:GO_Central.
DR GO; GO:0004613; F:phosphoenolpyruvate carboxykinase (GTP) activity; ISS:UniProtKB.
DR GO; GO:0106264; F:protein serine kinase activity (using GTP as donor); ISS:UniProtKB.
DR GO; GO:0071549; P:cellular response to dexamethasone stimulus; IBA:GO_Central.
DR GO; GO:0071333; P:cellular response to glucose stimulus; ISS:UniProtKB.
DR GO; GO:0032869; P:cellular response to insulin stimulus; ISS:UniProtKB.
DR GO; GO:0006094; P:gluconeogenesis; IBA:GO_Central.
DR GO; GO:0046327; P:glycerol biosynthetic process from pyruvate; IBA:GO_Central.
DR GO; GO:0070365; P:hepatocyte differentiation; IBA:GO_Central.
DR GO; GO:0006107; P:oxaloacetate metabolic process; ISS:UniProtKB.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; ISS:UniProtKB.
DR GO; GO:0043382; P:positive regulation of memory T cell differentiation; ISS:UniProtKB.
DR GO; GO:0019543; P:propionate catabolic process; IBA:GO_Central.
DR GO; GO:0046890; P:regulation of lipid biosynthetic process; ISS:UniProtKB.
DR GO; GO:0033993; P:response to lipid; IBA:GO_Central.
DR GO; GO:0042594; P:response to starvation; IBA:GO_Central.
DR CDD; cd00819; PEPCK_GTP; 1.
DR Gene3D; 3.40.449.10; -; 1.
DR Gene3D; 3.90.228.20; -; 1.
DR HAMAP; MF_00452; PEPCK_GTP; 1.
DR InterPro; IPR018091; PEP_carboxykin_GTP_CS.
DR InterPro; IPR013035; PEP_carboxykinase_C.
DR InterPro; IPR008209; PEP_carboxykinase_GTP.
DR InterPro; IPR035077; PEP_carboxykinase_GTP_C.
DR InterPro; IPR035078; PEP_carboxykinase_GTP_N.
DR InterPro; IPR008210; PEP_carboxykinase_N.
DR PANTHER; PTHR11561; PTHR11561; 1.
DR Pfam; PF00821; PEPCK_GTP; 1.
DR Pfam; PF17297; PEPCK_N; 1.
DR PIRSF; PIRSF001348; PEP_carboxykinase_GTP; 1.
DR SUPFAM; SSF68923; SSF68923; 1.
DR PROSITE; PS00505; PEPCK_GTP; 1.
PE 2: Evidence at transcript level;
KW Acetylation; Cytoplasm; Decarboxylase; Endoplasmic reticulum;
KW Gluconeogenesis; GTP-binding; Kinase; Lyase; Manganese; Metal-binding;
KW Nucleotide-binding; Phosphoprotein; Reference proteome; Transferase;
KW Ubl conjugation.
FT CHAIN 1..622
FT /note="Phosphoenolpyruvate carboxykinase, cytosolic [GTP]"
FT /id="PRO_0000103626"
FT REGION 457..487
FT /note="Omega-loop"
FT /evidence="ECO:0000250|UniProtKB:P07379"
FT ACT_SITE 288
FT /evidence="ECO:0000250|UniProtKB:P07379"
FT BINDING 87
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P07379"
FT BINDING 235..237
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P07379"
FT BINDING 244
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /evidence="ECO:0000250|UniProtKB:P07379"
FT BINDING 264
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /evidence="ECO:0000250|UniProtKB:P07379"
FT BINDING 286
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P07379"
FT BINDING 287..292
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000250|UniProtKB:P07379"
FT BINDING 311
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /evidence="ECO:0000250|UniProtKB:P07379"
FT BINDING 403..405
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P07379"
FT BINDING 405
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000250|UniProtKB:P07379"
FT BINDING 436
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000250|UniProtKB:P07379"
FT BINDING 530..533
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000250|UniProtKB:P07379"
FT MOD_RES 19
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P35558"
FT MOD_RES 70
FT /note="N6-acetyllysine; by p300/EP300"
FT /evidence="ECO:0000250|UniProtKB:P35558"
FT MOD_RES 71
FT /note="N6-acetyllysine; by p300/EP300"
FT /evidence="ECO:0000250|UniProtKB:P35558"
FT MOD_RES 90
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P35558"
FT MOD_RES 91
FT /note="N6-acetyllysine; by p300/EP300"
FT /evidence="ECO:0000250|UniProtKB:P35558"
FT MOD_RES 118
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2V4"
FT MOD_RES 178
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q16822"
FT MOD_RES 286
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q16822"
FT MOD_RES 473
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P07379"
FT MOD_RES 521
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P07379"
FT MOD_RES 594
FT /note="N6-acetyllysine; by p300/EP300"
FT /evidence="ECO:0000250|UniProtKB:P35558"
SQ SEQUENCE 622 AA; 69353 MW; DD7B678E3728992B CRC64;
MPPQLSDGLN YSAKIVRGSL DSLPQAVRSF VESSAKLCRP DQVHICDGSE EENRQLLSHM
EEEGVIKRLK KYDNCWLALT DPRDVARIES KTVIITREQR DTVPIPKNGL SQLGRWMSEE
DFEKAFNIRF PGCMKGRTMY VIPFSMGPLG SPLSKIGIEL TDSPYVVTSM RIMTRMGTSV
LEALGDGEFV KCLHSVGCPL PLKKPLVNNW ACNPELTLIA HLPDRREIIS FGSGYGGNSL
LGKKCFALRM ASRLAKEEGW LAEHMLILGI TNPKGQKKYF AAAFPSACGK TNLAMMNPTL
PGWKVECVGD DIAWMKFDQQ GNLRAINPEN GFFGVAPGTS VRTNPNAIKT IQKNTIFTNV
AETSDGGVYW EGIDQPLAAR VKLISWKGKE WDPKDGEPCA HPNSRFCTPA SQCPIIDPDW
ESPEGVPIEG IIFGGRRPVG VPLVYEALSW QHGVFVGAAM RSEATAAAEY KGKVIMHDPF
AMGPFFGYNF GQYLAHWLSM AQRPAAKLPK IFHVNWFRKD KAGRFLWPGF GENSRVLEWM
FNRVVGEGGA SVTPIGYIPD EDALDLRGLG DVDVKELFHI SKEFWEEEVE EIQKYLEEQV
NVDLPPEIKN QVLALKQRIS QM
