Literature summary for 1.14.13.39 extracted from

Guerby, P.; Tasta, O.; Swiader, A.; Pont, F.; Bujold, E.; Parant, O.; Vayssiere, C.; Salvayre, R.; Negre-Salvayre, A.
Role of oxidative stress in the dysfunction of the placental endothelial nitric oxide synthase in preeclampsia (2021), Redox Biol., 40, 101861 .

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Activating Compound

Activating Compound	Comment	Organism	Structure
Calmodulin	-	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
4-oxononenal	ONE, a highly bioreactive agent, able to inhibit eNOS activity and NO production. It can posttranslationally modify the enzyme in the placenta	Homo sapiens

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Ca2+	required	Homo sapiens
Fe2+	in the heme	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
2 L-arginine + 3 NADPH + 3 H+ + 4 O2	Homo sapiens	overall reaction	2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O	-	?
additional information	Homo sapiens	the bioavailability of substrates (L-arginine and O2) and the cofactor BH4 are important elements of enzyme activity	?	-	-

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P29474	-	-

Posttranslational Modification

Posttranslational Modification	Comment	Organism
lipoprotein	in PE placentas, eNOS can be posttranslationally modified by lipid peroxidation-derived aldehydes such as malondialdehyde or as 4-oxononenal (ONE) a highly bioreactive agent, able to inhibit eNOS activity and NO production. They covalently bind to the nucleophilic sulfhydryl and primary amine groups of proteins, forming Schiff bases, Michael adducts and protein crosslinks. The modification of proteins by lipid peroxidation products (LPPs) depends on their nature, expression and conformation, oxidative stress intensity and duration, cell type, local LPP concentration, and generates various biological responses from the expression of protective and adaptive factors to protein dysfunction, inflammation, senescence and apoptosis. The presence of LPPs in PE placentas, could be indicative of their premature senescence, in agreement with the hypothesis that accelerated placental aging is involved in PE pathophysiology via oxidative stress	Homo sapiens

Source Tissue

Source Tissue	Comment	Organism	Textmining
endothelium	-	Homo sapiens	-
placenta	-	Homo sapiens	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
2 L-arginine + 3 NADPH + 3 H+ + 4 O2	overall reaction	Homo sapiens	2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O	-	?
additional information	the bioavailability of substrates (L-arginine and O2) and the cofactor BH4 are important elements of enzyme activity	Homo sapiens	?	-	-
additional information	each monomer contains an oxygenase domain in the N-terminal section and a reductase domain in the C-terminal section. The oxygenase domain has binding sites for FAD, FMN and NADPH and is linked through a calmodulin recognition site to the reductase domain which has binding sites for heme, tetrahydrobiopterin (BH4), and L-arginine. In functional NOS, electrons are released by NADPH in the reductase domain and are transferred through FAD and FMN to the heme group of the opposite dimer. At this point, in the presence of L-arginine and the cofactor BH4, the electrons enable the reduction of O2 and the formation of NO and L-citrulline. The formation of NO requires electron flow, starting at the flavin level in the reductase domain, and ending at the heme level, on the oxygenase domain of the enzyme. The oxidized heme is able to bind O2 and L-arginine to synthesize NO and L-citrulline	Homo sapiens	?	-	-

Subunits

Subunits	Comment	Organism
homodimer	-	Homo sapiens

Synonyms

Synonyms	Comment	Organism
endothelial nitric oxide synthase	-	Homo sapiens
endothelial NOS	-	Homo sapiens
eNOS	-	Homo sapiens
NOS3	-	Homo sapiens

Cofactor

Cofactor	Comment	Organism	Structure
FAD	-	Homo sapiens
FMN	-	Homo sapiens
heme	-	Homo sapiens
NADH	-	Homo sapiens

General Information

General Information	Comment	Organism
malfunction	role of oxidative stress in the dysfunction of the placental endothelial nitric oxide synthase in preeclampsia (PE), multifactorial pregnancy disease, characterized by new-onset gestational hypertension with (or without) proteinuria or end-organ failure, exclusively observed in humans. PE pathophysiology can result from abnormal placentation due to a defective trophoblastic invasion and an impaired remodeling of uterine spiral arteries, leading to a poor adaptation of utero-placental circulation. This would be associated with hypoxia/ reoxygenation phenomena, oxygen gradient fluctuations, altered antioxidant capacity, oxidative stress, and reduced nitric oxide (NO) bioavailability. This results in part from the reaction of NO with the radical anion superoxide, which produces peroxynitrite ONOO-, a powerful pro-oxidant and inflammatory agent. Another mechanism is the progressive inhibition of the placental endothelial nitric oxide synthase (eNOS) by oxidative stress, which results in eNOS uncoupling via several events such as a depletion of the eNOS substrate L-arginine due to increased arginase activity, an oxidation of the eNOS cofactor tetrahydrobiopterin (BH4), or eNOS posttranslational modifications (for instance by S-glutathionylation). The uncoupling of eNOS triggers a switch of its activity from a NO-producing enzyme to a NADPH oxidase-like system generating superoxide, thereby potentiating ROS production and oxidative stress. Moreover, in PE placentas, eNOS can be posttranslationally modified by lipid peroxidation-derived aldehydes such as 4-oxononenal (ONE) a highly bioreactive agent, able to inhibit eNOS activity and NO production. Analysis of the dysfunction of placental eNOS evoked by oxidative stress and lipid peroxidation products, and the potential consequences on PE pathogenesis, detailed overview. Oxidative stress is thought to play a pivotal role in the decreased NO bioavailability in PE pathophysiology, via several mechanisms including an inhibition of eNOS (eNOS uncoupling) and subsequent defect of NO biosynthesis, or through the formation of peroxynitrite, via the reaction of NO with the radical anion superoxide. eNOS inhibition is associated with a decrease in endothelial-dependent relaxation in vitro and in vivo. Therapeutic perspectives targeting oxidative stress and NO/eNOS dysfunction	Homo sapiens
physiological function	in endothelium and placenta, NO is biosynthesized by the endothelial nitric oxide synthase (eNOS), and confers to endothelium its vasorelaxing and anti-aggregant properties. NO participates to placentation and the synthesis of the vascular endothelial growth factor (VEGF). NO plays an essential role in vascular homeostasis due to its vasodilatory effect. NO is synthesized by nitric oxide synthases (NOS), from L-arginine and molecular oxygen (O2). In short, the reaction allowing NO synthesis can be compared to two monooxygenation reactions. The first reaction consists of the oxidation of L-arginine. This reaction produces an intermediate, -OH-L-arginine, which is rapidly oxidized into L-citrulline. These two oxygenation reactions occur in parallel with a concomitant conversion of NADPH to NADP+. The electrons are supplied by NADPH, transferred to flavins (FAD and FMN) and calmodulin, then presented to heme, the catalytic center. Three NOS isoforms have been characterized, the neuronal NOS (nNOS or NOS1), the inducible NOS (iNOS or NOS2) and the endothelial NOS (eNOS or NOS3). NO released by endothelial cells in vivo causes a permanent vasodilation of the arterial tone that helps to regulate arterial pressure. During pregnancy, NO has a primary role in vasodilation and blood pressure regulation, placentation and VEGF synthesis. Oxidative stress impact on NO bioavailability, detailed overview. S-Glutathionylation can be promoted by NO, via mechanisms implicating S-nitrosoglutathione (GSNO) and thiyl radicals. S-glutathionylated proteins reversibly accumulate under oxidative stress conditions and can be rapidly reduced by reducing agents and glutaredoxins. S-glutathionylation alters the structure, folding and function of proteins, and can be considered as an adaptative and protective mechanism against the irreversible oxidation of cysteine residues during oxidative stress	Homo sapiens

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Release 2023.1 (January 2023)