Atherosclerosis
George Feuer, Felix A. de la Iglesia in Molecular Biochemistry of Human Disease, 2020
Another aspect of the endoplasmic reticulum involvement is its role in lipid metabolism. Serum cholesterol levels are dependent on the action of microsomal hydroxylases including cholesterol 7α-hydroxylation, representing the first step in the conversion of cholesterol to bile acids.77 Impaired enzyme function can lead to progressive accumulation of cholesterol in the liver and other tissues (Table 2). Excessive amounts of lipids accumulate in the endoplasmic reticulum membranes and disturb their normal fluidic structure. This may result in impaired mixed function oxidase system with accompanying increased nonspecific hydroxy lation and peroxidation. Generation of lipid peroxides can damage endothelial prostacyclin synthetase, leading to suppression of PGI2 in the heart, aorta, and mesenteric arteries.248,322 Under the same conditions, the production of thromboxane A2 by platelets is enhanced contributing to the progression of atherosclerotic lesions.
Ascorbate as an Enzyme Cofactor
Qi Chen, Margreet C.M. Vissers in Vitamin C, 2020
The active site of the 2-OGDDs is highly conserved and contains a nonheme Fe bound through three-point coordination with two histidine residues and an aspartic acid or glutamic acid, with the remaining three coordination sites occupied by water ligands [89,90]. The enzymes use O2 and 2-oxoglutarate (2-OG) as substrates to catalyze the hydroxylation of the target substrate [57,58,90]. During the reactive cycle, the water ligands are displaced by 2-OG at two positions and by O2 at the final available site (see Figure 5.2). The hydroxylation of the target substrate occurs by radical reactions that involve the formation of a superoxide radical that decarboxylates 2-OG to produce succinate, CO2, and a ferryl (FeIV)-oxo intermediate. This intermediate is able to hydroxylate the substrate by radical transfer, finally regenerating the Fe2+ active center and releasing the hydroxylated product, succinate, and CO2 [57,58,89] (Figure 5.1).
Cytochrome P450-Dependent Metabolism of Drugs and Carcinogens in Skin
Rhoda G. M. Wang, James B. Knaak, Howard I. Maibach in Health Risk Assessment, 2017
Depending on the particular reaction and the nature of various unstable intermediates, different types of Phase I reactions can occur in skin.18 However, in a typical Phase I reaction, hydroxylation of the substrate occurs at a carbon atom. In the first step, the substrate binds to the protein moiety of the oxidized P450, followed by one electron reduction of the heme iron (Fe3+) provided by NADPH-P450 reductase. The reduced P450-substrate complex, thus formed, binds to molecular oxygen and utilizes another electron from NADPHP450 reductase. During this process, the substrate is attacked by the oxygen molecule and thereby one oxygen atom is inserted into the substrate which is released from the enzyme as the hydroxylated product, while the second oxygen atom yields water. Based on this process, this enzyme reaction has been termed as a “mixed-function oxidase”- or a “monooxygenase”- reaction.
In silico prediction of post-translational modifications in therapeutic antibodies
Published in mAbs, 2022
Hydroxylation is an enzymatic modification that is catalyzed by hydroxylases. Hydroxylation can occur at arginine, tyrosine, Trp, and phenylalanine, but it is more common for Pro and Lys.121 During hydroxylation, a hydroxyl (OH) group is added to Pro or Lys residues. As a result, Pro is converted to 3-hydroxyPro or 4-hydroxyPro, whereas Lys is converted to 5-hydroxyLys.122 Hydroxylation of Lys and Pro residues at consensus motifs (Xaa-Lys-Gly or Xaa-Pro-Gly) is common in collagen, where hydroxylation helps stabilize the collagen triple-helix.123 Common parameters for designing hydroxylation predictors include solvent exposure, intrinsic disorder, hydrophilicity, and sequence.122,123 Hydroxylation sites tend to be disordered, exposed, and enriched with Pro and Gly residues.124
Promoting vascularization for tissue engineering constructs: current strategies focusing on HIF-regulating scaffolds
Published in Expert Opinion on Biological Therapy, 2019
Tilman U. Esser, Kaveh Roshanbinfar, Felix B. Engel
The importance of the ferrous ion within the catalytic domain of PHDs is further illustrated by the fact that hydroxylase activity is highly sensitive to chelating agents. Deferoxamine (DFO) is an FDA-approved iron chelator used for the treatment of acute or chronic iron overload and thalassemia. It has gained further attention due to its ability to stabilize HIF-1α [112], making it an interesting candidate for inducing vascularization. Indeed, DFO administration has been shown to induce the expression of angiogenic factors and vessel formation [113,114], as well as other downstream HIF-targets [115]. Accordingly, a clinical trial to examine the efficacy of DFO for wound healing in diabetic patients has recently been registered (ClinicalTrials.gov Identifier: NCT03137966).
Chemical pharmacotherapy for the treatment of orthostatic hypotension
Published in Expert Opinion on Pharmacotherapy, 2019
Approximately one-third of patients with persistent OH have nOH, which is a cardinal manifestation of sympathetic adrenergic failure [34]. NOH results from deficient neurotransmission of norepinephrine, which is the primary neurotransmitter released at sympathetic postganglionic nerve terminals. This can occur at the level of the central or the peripheral nervous system. Congenital adrenergic failure occurs in dopamine β-hydroxylase deficiency. Central adrenergic failure occurs in diseases such as multiple system atrophy (MSA) that destroy brain stem or spinal cord pathways that mediate sympathetic outflow. Ganglionic adrenergic failure occurs in diseases such as autoimmune autonomic ganglionopathy in patients with α3-ganglionic neuronal acetylcholine receptor antibodies which interrupt sympathetic neurotransmission in the sympathetic chain ganglia. Peripheral adrenergic failure occurs in diseases that impair postganglionic sympathetic neurons innervating vascular adrenoceptors. Examples include PAF, Parkinson’s disease (PD), Lewy body dementia, amyloid autonomic neuropathy, and diabetic autonomic neuropathy.