Diacylglycerol kinase

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Diacylglycerol kinase
Soluble diacylglycerol kinase DgkB from Staphylococcus aureus.png
DgkB, soluble DAGK from Staphylococcus aureus. α-helices in red, β-strands in yellow, coils in green.
Identifiers
EC no. 2.7.1.107
CAS no. 60382-71-0
Databases
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BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
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PMC articles
PubMed articles
NCBI proteins
Prokaryotic diacylglycerol kinase
Identifiers
SymbolDAGK_prokar
Pfam PF01219
InterPro IPR000829
PROSITE PDOC00820
OPM superfamily 196
OPM protein 4d2e
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Diacylglycerol kinase catalytic domain
Identifiers
SymbolDAGK_cat
Pfam PF00781
Pfam clan CL0240
InterPro IPR001206
SMART DAGKc
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Diacylglycerol kinase accessory domain
Identifiers
SymbolDAGK_acc
Pfam PF00609
InterPro IPR000756
SMART DAGKa
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Diacylglycerol kinase (DGK or DAGK) is a family of enzymes that catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA), utilizing ATP as a source of the phosphate. [1] In non-stimulated cells, DGK activity is low, allowing DAG to be used for glycerophospholipid biosynthesis, but on receptor activation of the phosphoinositide pathway, DGK activity increases, driving the conversion of DAG to PA. As both lipids are thought to function as bioactive lipid signaling molecules with distinct cellular targets, DGK therefore occupies an important position, effectively serving as a switch by terminating the signalling of one lipid while simultaneously activating signalling by another. [2]

Contents

In bacteria, DGK is very small (13 to 15 kDa) membrane protein which seems to contain three transmembrane domains. [3] The best conserved region is a stretch of 12 residues which are located in a cytoplasmic loop between the second and third transmembrane domains. Some Gram-positive bacteria also encode a soluble diacylglycerol kinase capable of reintroducing DAG into the phospholipid biosynthesis pathway. DAG accumulates in Gram-positive bacteria as a result of the transfer of glycerol-1-phosphate moieties from phosphatidylglycerol to lipotechoic acid. [4]

Mammalian DGK Isoforms

Currently, nine members of the DGK family have been cloned and identified. Although all family members have conserved catalytic domains and two cysteine rich domains, they are further classified into five groups according to the presence of additional functional domains and substrate specificity. [5] These are as follows:

Clinical Significance

In a phenotypic screen for small molecules that could stimulate interleukin-2 (IL2) secretion from primary T cells in the presence or absence of PD-1 suppression, BMS-684 was found to be able to act as a T cell checkpoint inhibitor. Further optimization led to the compound BMS-496. Using lipid-based photoaffinity probes, DGKα was identified as the primary target of BMS-496. BMS-496 induces translocation of DGKα to the plasma membrane. Further study found that these compounds also inhibit DGKζ and similarly induce translocation of DGKζ to the plasma membrane. Preclinical studies found that this strategy of dual DGKα/ζ inhibition can potentiate the anticancer effects of PD-1 blockade. [6] [7]

References

  1. Shulga, Yulia V.; Topham, Matthew K.; Epand, Richard M. (2011). "Regulation and Functions of Diacylglycerol Kinases". Chemical Reviews. 111 (10): 6186–6208. doi:10.1021/cr1004106. PMID   21800853.
  2. Mérida I, Avila-Flores A, Merino E (January 2008). "Diacylglycerol kinases: at the hub of cell signalling". The Biochemical Journal. 409 (1): 1–18. doi:10.1042/BJ20071040. PMID   18062770.
  3. Smith RL, O'Toole JF, Maguire ME, Sanders CR (September 1994). "Membrane topology of Escherichia coli diacylglycerol kinase". Journal of Bacteriology. 176 (17): 5459–65. doi:10.1128/jb.176.17.5459-5465.1994. PMC   196734 . PMID   8071224.
  4. Miller DJ, Jerga A, Rock CO, White SW (July 2008). "Analysis of the Staphylococcus aureus DgkB structure reveals a common catalytic mechanism for the soluble diacylglycerol kinases". Structure. 16 (7): 1036–46. doi:10.1016/j.str.2008.03.019. PMC   2847398 . PMID   18611377.
  5. van Blitterswijk WJ, Houssa B (October 2000). "Properties and functions of diacylglycerol kinases". Cellular Signalling. 12 (9–10): 595–605. doi: 10.1016/s0898-6568(00)00113-3 . PMID   11080611.
  6. Wichroski, Michael; Benci, Joseph; Liu, Si-Qi; Chupak, Louis; Fang, Jie; Cao, Carolyn; Wang, Cindy; Onorato, Joelle; Qiu, Hongchen; Shan, Yongli; Banas, Dana; Powles, Ryan; Locke, Gregory; Witt, Abigail; Stromko, Caitlyn (2023-10-25). "DGKα/ζ inhibitors combine with PD-1 checkpoint therapy to promote T cell–mediated antitumor immunity" . Science Translational Medicine. 15 (719) eadh1892. doi:10.1126/scitranslmed.adh1892. ISSN   1946-6234. PMID   37878674.
  7. Chupak, Louis; Wichroski, Michael; Zheng, Xiaofan; Ding, Min; Martin, Scott; Allard, Christopher; Shi, Jianliang; Gentles, Robert; Meanwell, Nicholas A.; Fang, Jie; Tenney, Daniel; Tokarski, John; Cao, Carolyn; Wee, Susan (2023-07-13). "Discovery of Potent, Dual-Inhibitors of Diacylglycerol Kinases Alpha and Zeta Guided by Phenotypic Optimization". ACS Medicinal Chemistry Letters. 14 (7): 929–935. doi:10.1021/acsmedchemlett.3c00063. ISSN   1948-5875. PMC   10351048 . PMID   37465293.