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Literature summary for 1.1.1.3 extracted from

  • Bagatin, M.C.; Pimentel, A.L.; Biavatti, D.C.; Basso, E.A.; Kioshima, E.S.; Seixas, F.A.V.; Gauze, G.F.
    Targeting the homoserine dehydrogenase of Paracoccidioides species for treatment of systemic fungal infections (2017), Antimicrob. Agents Chemother., 61, e00165-17 .
    View publication on PubMedView publication on EuropePMC

Inhibitors

Inhibitors Comment Organism Structure
4-(4-hydroxy-3-isopropylphenylthio)-2-isopropylphenol
-
Paracoccidioides brasiliensis
4-(4-hydroxy-3-isopropylphenylthio)-2-isopropylphenol
-
Paracoccidioides lutzii
Amphotericin B MIC value against strain Pb18 is 0.12 mg/ml Paracoccidioides brasiliensis
Amphotericin B MIC value against strain Pb18 is 0.06 mg/ml Paracoccidioides lutzii
itraconazole MIC value against strain Pb18 is 0.007 mg/ml Paracoccidioides brasiliensis
itraconazole MIC value against strain Pb18 is 0.007 mg/ml Paracoccidioides lutzii
additional information molecular docking simulations and inhibitor screening, virtual screening simulations with 187841 molecules purchasable from the Zinc database. 14 molecules are selected and analyzed by the use of absorption, distribution, metabolism, excretion, and toxicity criteria, resulting in four compounds for in vitro assays. Synergistic effects of HS1 and HS2 in combination with itraconazole against Paracoccidioides brasiliensis. Zinc1531037 and Zinc52986906 are not inhibitory Paracoccidioides brasiliensis
additional information molecular docking simulations and inhibitor screening, virtual screening simulations with 187841 molecules purchasable from the Zinc database. 14 Molecules are selected and analyzed by the use of absorption, distribution, metabolism, excretion, and toxicity criteria, resulting in four compounds for in vitro assays. Zinc1531037 and Zinc52986906 are not inhibitory Paracoccidioides lutzii
Zinc203432 MIC value is 0.032 mg/ml Paracoccidioides brasiliensis
Zinc203432 MIC value is 0.064 mg/ml Paracoccidioides lutzii
Zinc273730 MIC value is 0.064 mg/ml Paracoccidioides brasiliensis
Zinc273730 MIC value is 0.064. Zinc273730 makes important contacts with Gly215, Tyr216, Thr217, and Glu218 Paracoccidioides lutzii

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
L-homoserine + NAD+ Paracoccidioides brasiliensis
-
L-aspartate 4-semialdehyde + NADH + H+
-
?
L-homoserine + NAD+ Paracoccidioides lutzii
-
L-aspartate 4-semialdehyde + NADH + H+
-
?
L-homoserine + NAD+ Paracoccidioides lutzii Pb01
-
L-aspartate 4-semialdehyde + NADH + H+
-
?
L-homoserine + NAD+ Paracoccidioides brasiliensis PB18
-
L-aspartate 4-semialdehyde + NADH + H+
-
?

Organism

Organism UniProt Comment Textmining
Paracoccidioides brasiliensis C1G1C3
-
-
Paracoccidioides brasiliensis PB18 C1G1C3
-
-
Paracoccidioides lutzii C1GTZ6
-
-
Paracoccidioides lutzii Pb01 C1GTZ6
-
-

Reaction

Reaction Comment Organism Reaction ID
L-homoserine + NAD(P)+ = L-aspartate 4-semialdehyde + NAD(P)H + H+ proposed reaction mechanisms of hydride transfer from L-homoserine in the active site of Paracoccidioides brasiliensis homoserine dehydrogenase (HSD), Glu218 accepts a proton from the hydroxyl group of L-homoserine, which donates a hydride to the nC-4 carbon of NAD+. Lys233, Lys122, and the water molecule at position 374 (Wat374) serve to bind the substrate Paracoccidioides brasiliensis

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
L-homoserine + NAD+
-
Paracoccidioides brasiliensis L-aspartate 4-semialdehyde + NADH + H+
-
?
L-homoserine + NAD+
-
Paracoccidioides lutzii L-aspartate 4-semialdehyde + NADH + H+
-
?
L-homoserine + NAD+
-
Paracoccidioides lutzii Pb01 L-aspartate 4-semialdehyde + NADH + H+
-
?
L-homoserine + NAD+
-
Paracoccidioides brasiliensis PB18 L-aspartate 4-semialdehyde + NADH + H+
-
?

Synonyms

Synonyms Comment Organism
HSD
-
Paracoccidioides brasiliensis
HSD
-
Paracoccidioides lutzii

Cofactor

Cofactor Comment Organism Structure
NAD+
-
Paracoccidioides brasiliensis
NAD+
-
Paracoccidioides lutzii
NADH
-
Paracoccidioides brasiliensis
NADH
-
Paracoccidioides lutzii

General Information

General Information Comment Organism
evolution enzyme homoserine dehydrogenase (HSD) belongs to the family of oxidoreductases and is essential for the biosynthesis of threonine (Thr), methionine (Met), and lysine (Lys) in the metabolic pathway of fungi and plants Paracoccidioides brasiliensis
evolution enzyme homoserine dehydrogenase (HSD) belongs to the family of oxidoreductases and is essential for the biosynthesis of threonine (Thr), methionine (Met), and lysine (Lys) in the metabolic pathway of fungi and plants Paracoccidioides lutzii
additional information structure homology modeling of enzyme with bound substrate NAD+ and L-homoserine using the Saccharomyces cerevisiae enzyme (PDB ID 1EBU) as template, binding analysis, overview. The model with the best output is subjected to gradient minimization, redocking, and molecular dynamics simulation Paracoccidioides brasiliensis