Literature summary for 6.1.1.2 extracted from

Ahn, Y.H.; Park, S.; Choi, J.J.; Park, B.K.; Rhee, K.H.; Kang, E.; Ahn, S.; Lee, C.H.; Lee, J.S.; Inn, K.S.; Cho, M.L.; Park, S.H.; Park, K.; Park, H.J.; Lee, J.H.; Park, J.W.; Kwon, N.H.; Shim, H.; Han, B.W.; Kim, P.; Lee, J.Y.; Jeon, Y.; Huh, J.W.; Jin, M.; Kim, S.
Secreted tryptophanyl-tRNA synthetase as a primary defence system against infection (2016), Nat. Microbiol., 2, 16191 .

Search for more literature for 6.1.1.2

Cloned(Commentary)

Cloned (Comment)	Organism
gene WARS, constitutive expression	Homo sapiens

Protein Variants

Protein Variants	Comment	Organism
A7D	site-directed mutagenesis, the mutant shows reduced induction of TNF-alpha and MIP-1alpha production compared to wild-type	Homo sapiens
E11L	site-directed mutagenesis, the mutant shows reduced induction of TNF-alpha and MIP-1alpha production compared to wild-type	Homo sapiens
E35G	site-directed mutagenesis, the mutant shows similar induction of TNF-alpha and MIP-1alpha production compared to wild-type	Homo sapiens
L10D	site-directed mutagenesis, the mutant shows reduced induction of TNF-alpha and MIP-1alpha production compared to wild-type	Homo sapiens
L22G	site-directed mutagenesis, the mutant shows reduced induction of TNF-alpha and MIP-1alpha production compared to wild-type	Homo sapiens
L9D	site-directed mutagenesis, the mutant shows reduced induction of TNF-alpha and MIP-1alpha production compared to wild-type	Homo sapiens
M42D	site-directed mutagenesis, the mutant shows reduced induction of TNF-alpha and MIP-1alpha production compared to wild-type	Homo sapiens
additional information	generation of N-terminal 51 amino acid-deleted enzyme WRS mutant (mDELTAN51-WRS). The full-length wild-type enzyme, but not mini-WRS, activates macrophages to prime innate immune responses. The N-terminal 47 aa that are lacking in mini-WRS may be necessary for the correct orientation of the TLR4-MD2 dimers that is required for the activation of downstream signal pathways. Reduced levels of TNF-alpha and MIP-1alpha in culture supernatants of bone marrow derived macrophages treated with WRS enzyme mutants, except for mutant E35G causing slightly increased levels	Homo sapiens
N152G	site-directed mutagenesis, the mutant shows reduced induction of TNF-alpha and MIP-1alpha production compared to wild-type	Homo sapiens
N30G	site-directed mutagenesis, the mutant shows reduced induction of TNF-alpha and MIP-1alpha production compared to wild-type	Homo sapiens
Q145G	site-directed mutagenesis, the mutant shows reduced induction of TNF-alpha and MIP-1alpha production compared to wild-type	Homo sapiens
T18G	site-directed mutagenesis, the mutant shows reduced induction of TNF-alpha and MIP-1alpha production compared to wild-type	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
additional information	the full-length-WRS-induced TNF-alpha and MIP-1alpha production is significantly inhibited when TLR4, MD2, and TLR2 (to lesser degree) are suppressed	Homo sapiens
additional information	the full-length-WRS-induced TNF-alpha and MIP-1alpha production is significantly inhibited when TLR4, MD2, and TLR2 (to lesser degree) are suppressed	Mus musculus

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
cytoplasm	-	Homo sapiens	5737	-
cytoplasm	-	Mus musculus	5737	-
extracellular	the enzyme is secreted	Mus musculus	-	-
extracellular	the enzyme is secreted in N-terminal truncated form or in full-length form. The full-length wild-type enzyme, but not the short form, is rapidly secreted upon pathogen infection to prime innate immunity. Blood levels of full-length WRS are increased in sepsis patients, but not in those with sterile inflammation. Full-length WRS is secreted from monocytes and directly bound to macrophages via a toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex to induce phagocytosis and chemokine production	Homo sapiens	-	-

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Mg2+	required	Homo sapiens
Mg2+	required	Mus musculus

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
ATP + L-tryptophan + tRNATrp	Homo sapiens	-	AMP + diphosphate + L-tryptophyl-tRNATrp	-	?
ATP + L-tryptophan + tRNATrp	Mus musculus	-	AMP + diphosphate + L-tryptophyl-tRNATrp	-	?
ATP + L-tryptophan + tRNATrp	Mus musculus C57BL/6	-	AMP + diphosphate + L-tryptophyl-tRNATrp	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P23381	-	-
Mus musculus	P32921	-	-
Mus musculus C57BL/6	P32921	-	-

Source Tissue

Source Tissue	Comment	Organism	Textmining
cell culture	peripheral blood mononuclear cells	Homo sapiens	-
macrophage	-	Homo sapiens	-
macrophage	-	Mus musculus	-
monocyte	-	Homo sapiens	-
monocyte	-	Mus musculus	-
additional information	full-length WRS is secreted from monocytes and directly bound to macrophages via a toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex to induce phagocytosis and chemokine production	Homo sapiens	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
ATP + L-tryptophan + tRNATrp	-	Homo sapiens	AMP + diphosphate + L-tryptophyl-tRNATrp	-	?
ATP + L-tryptophan + tRNATrp	-	Mus musculus	AMP + diphosphate + L-tryptophyl-tRNATrp	-	?
ATP + L-tryptophan + tRNATrp	-	Mus musculus C57BL/6	AMP + diphosphate + L-tryptophyl-tRNATrp	-	?
additional information	potential complex formation between TLR4-MD2 and the WRS monomer, putative binding model of TLR4-MD2 with the enzyme WRS homodimer based on a protein-protein docking study, complex crystal structure analysis, overview	Homo sapiens	?	-	?

Synonyms

Synonyms	Comment	Organism
Tryptophanyl-tRNA synthetase	-	Homo sapiens
Tryptophanyl-tRNA synthetase	-	Mus musculus
WARS	-	Homo sapiens
WRS	-	Homo sapiens
WRS	-	Mus musculus

Cofactor

Cofactor	Comment	Organism	Structure
ATP	-	Homo sapiens
ATP	-	Mus musculus

General Information

General Information	Comment	Organism
malfunction	the full-length-WRS-induced TNF-alpha and MIP-1alpha production is significantly inhibited when TLR4, MD2, and TLR2 (to lesser degree) are suppressed, full-length-WRS-induced neutrophil infiltration is almost ablated in the TLR4-/- and MD2-/- mice, and partially reduced in TLR2-/- mice. Although truncated WRS mutant lacking N47 can bring the two TLR4-MD2 complexes into proximity through homodimerization of the WRS catalytic domain, it may not be able to induce the functional dimerization of TLR4-MD2 to activate downstream signalling	Mus musculus
malfunction	the full-length-WRS-induced TNF-alpha and MIP-1alpha production is significantly inhibited when TLR4, MD2, and TLR2 (to lesser degree) are suppressed, human full-length-WRS-induced neutrophil infiltration is almost ablated in the TLR4-/- and MD2-/- mice, and partially reduced in TLR2-/- mice. Although truncated WRS mutant lacking N47 can bring the two TLR4-MD2 complexes into proximity through homodimerization of the WRS catalytic domain, it may not be able to induce the functional dimerization of TLR4-MD2 to activate downstream signalling	Homo sapiens
physiological function	the secreted tryptophanyl-tRNA synthetase is a primary defence system against infection, it functions as an intrinsic defensive factor against infection. Administration of full-length murine WRS into Salmonella typhimurium-infected mice reduces the levels of bacteria and improves mouse survival, whereas its titration with the specific antibody aggravates the infection. Full-length WRS protects mice from typhimurium infection-induced lethality. The enzyme is secreted in N-terminal truncated form or in full-length form, the full-length wild-type enzyme, but not the short form, is rapidly secreted upon pathogen infection to prime innate immunity. Proposed working mechanism of full-length-WRS for TLR4-MD2 activation, overview	Mus musculus
physiological function	the secreted tryptophanyl-tRNA synthetase is a primary defence system against infection, it functions as an intrinsic defensive factor against infection. Full-length WRS responds promptly to pathogens before the onset of innate immune responses. Prompt secretion of enzyme WRS from cultured human peripheral blood mononuclear cells (PBMCs) following infection with Salmonella typhimurium, Escherichia coli, Listeria monocytogenes, Staphylococcus aureus, and Candida albicans. Human full-length-WRS as an endogenous ligand of TLR4, which promptly triggers innate immunity against infection. Proposed working mechanism of full-length-WRS for TLR4-MD2 activation, overview	Homo sapiens

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Release 2023.1 (January 2023)