Diacylglycerol kinase

Class of enzymes

Diacylglycerol kinase

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
IntEnz| IntEnz view
BRENDA| BRENDA entry
ExPASy| NiceZyme view
KEGG| KEGG entry
MetaCyc| metabolic pathway
PRIAM| profile
PDB structures| RCSB PDB PDBe PDBsum
| Search

PMC| articles
PubMed| articles
NCBI| proteins

Protein family

Prokaryotic diacylglycerol kinase

Identifiers
Symbol| DAGK_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

Protein domain

Diacylglycerol kinase catalytic domain

Identifiers
Symbol| DAGK_cat
Pfam| PF00781
Pfam clan| CL0240
InterPro| IPR001206
SMART| DAGKc
| Available protein structures:

Pfam | structures / ECOD
PDB| RCSB PDB; PDBe; PDBj
PDBsum| structure summary

Protein domain

Diacylglycerol kinase accessory domain

Identifiers
Symbol| DAGK_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]

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

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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:

* Type 1 - DGK-α, DGK-β, DGK-γ - contain EF-hand motifs and a recoverin homology domain
* Type 2 - DGK-δ, DGK-η - contain a pleckstrin homology domain
* Type 3 - DGK-ε - has specificity for arachidonate-containing DAG
* Type 4 - DGK-ζ, DGK-ι - contain a MARCKS homology domain, ankyrin repeats, a C-terminal nuclear localisation signal, and a PDZ-binding motif.
* Type 5 - DGK-θ - contains a third cysteine-rich domain, a pleckstrin homology domain and a proline rich region

## Clinical Significance

[edit]

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

[edit]

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 11080611.9–10&rft.pages=595-605&rft.date=2000-10&rft_id=info:doi/10.1016/s0898-6568(00)00113-3&rft_id=info:pmid/11080611&rft.aulast=van+Blitterswijk&rft.aufirst=WJ&rft.au=Houssa,+B&rft_id=https://doi.org/10.1016%2Fs0898-6568%2800%2900113-3&rfr_id=info:sid/en.wikipedia.org:Diacylglycerol+kinase" class="Z3988">
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). 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.

## External links

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* Diacylglycerol+Kinase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
* EC 2.7.1.107

* v
* t
* e

* Metabolism: lipid metabolism
* phospholipids

Anabolism|

* to diacylglycerol: Acyltransferase
* Phosphatidate phosphatase
* 2C

* Choline kinase
* CHKA
* CHKB
* Choline-phosphate cytidylyltransferase

* phosphatidylinositol glycan anchor biosynthesis:
* PIGA
* PIGB
* PIGC
* PIGF
* PIGG
* PIGH
* PIGK
* PIGL
* PIGM
* PIGN
* PIGO
* PIGP
* PIGQ
* PIGS
* PIGT
* PIGU
* PIGV
* PIGW
* PIGX
* PIGY
* PIGZ

* cardiolipin: Tafazzin

Catabolism|

* Phospholipase C

* Diacylglycerol kinase
* DGKA
* DGKB
* DGKD
* DGKE
* DGKG
* DGKH
* DGKI
* DGKK
* DGKQ
* DGKZ

* Phosphoric monoester hydrolases
* Inositol-phosphate phosphatase

* v
* t
* e

Transferases: phosphorus-containing groups (EC 2.7)

2.7.1-2.7.4:
phosphotransferase/kinase
(PO4)|

| 2.7.1: OH acceptor|

* Hexo-
* Gluco-
* Fructo-
* Hepatic
* Galacto-
* Phosphofructo-
* 1
* Liver
* Muscle
* Platelet
* 2
* Riboflavin
* Shikimate
* Thymidine
* ADP-thymidine
* NAD+
* Glycerol
* Pantothenate
* Mevalonate
* Pyruvate
* Deoxycytidine
* PFP
* Diacylglycerol
* Phosphoinositide 3
* Class I PI 3
* Class II PI 3
* Sphingosine
* Glucose-1,6-bisphosphate synthase

|

2.7.2: COOH acceptor|

* Phosphoglycerate
* Aspartate kinase

2.7.3: N acceptor|

* Creatine

2.7.4: PO4 acceptor|

* Phosphomevalonate
* Adenylate
* Nucleoside-diphosphate
* Uridylate
* Guanylate
* Thiamine-diphosphate

2.7.6: diphosphotransferase
(P2O7)|

* Ribose-phosphate diphosphokinase
* Thiamine diphosphokinase

2.7.7: nucleotidyltransferase
(PO4-nucleoside)|

| Polymerase|

| DNA polymerase|

DNA-directed DNA polymerase
I/A

Taq
II/B

Pfu
III/C
IV/X

TDT
V/Y

RNA-directed DNA polymerase
Reverse transcriptase

Telomerase

|

RNA polymerase|

Template-directed
RNA polymerase I

III

ssRNAP

POLRMT
Primase

PrimPol
RNA-dependent RNA polymerase
Polyadenylation
PAP
PNPase

Phosphorolytic
3' to 5' exoribonuclease|

* RNase PH
* PNPase

Nucleotidyltransferase|

* UTP—glucose-1-phosphate uridylyltransferase
* Galactose-1-phosphate uridylyltransferase

Guanylyltransferase|

* mRNA capping enzyme

Other|

* Recombinase (Integrase)
* Transposase

2.7.8: miscellaneous|

| Phosphatidyltransferases|

* CDP-diacylglycerol—glycerol-3-phosphate 3-phosphatidyltransferase
* CDP-diacylglycerol—serine O-phosphatidyltransferase
* CDP-diacylglycerol—inositol 3-phosphatidyltransferase
* CDP-diacylglycerol—choline O-phosphatidyltransferase

|

Glycosyl-1-phosphotransferase|

* N-acetylglucosamine-1-phosphate transferase

2.7.10-2.7.13: protein kinase
(PO4; protein acceptor)|

| 2.7.10: protein-tyrosine|

* see tyrosine kinases

|

2.7.11: protein-serine/threonine|

* see serine/threonine-specific protein kinases

2.7.12: protein-dual-specificity|

* see serine/threonine-specific protein kinases

2.7.13: protein-histidine|

* Protein-histidine pros-kinase
* Protein-histidine tele-kinase
* Histidine kinase

* v
* t
* e

Enzymes

Activity|

* Active site
* Binding site
* Catalytic triad
* Oxyanion hole
* Enzyme promiscuity
* Diffusion-limited enzyme
* Cofactor
* Enzyme catalysis

Regulation|

* Allosteric regulation
* Cooperativity
* Enzyme inhibitor
* Enzyme activator

Classification|

* EC number
* Enzyme superfamily
* Enzyme family
* List of enzymes

Kinetics|

* Enzyme kinetics
* Eadie–Hofstee diagram
* Hanes–Woolf plot
* Lineweaver–Burk plot
* Michaelis–Menten kinetics

Types|

* EC1 Oxidoreductases (list)
* EC2 Transferases (list)
* EC3 Hydrolases (list)
* EC4 Lyases (list)
* EC5 Isomerases (list)
* EC6 Ligases (list)
* EC7 Translocases (list)

Portal:

* Biology

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