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Impairment of Lipid Metabolism in Ischemic and Reperfused Myocardial Tissue
Published in Samuel Sideman, Rafael Beyar, Analysis and Simulation of the Cardiac System — Ischemia, 2020
Ger J. van der Vusse, Marc van Bilsen, Robert S. Reneman
With respect to the question about the mechanism underlying the accumulation of NEFA, in particular arachidonic acid, in ischemic tissue, no definitive theory can be offered. At this moment, the most feasible hypothesis is impaired turnover of cellular phosphoglycerides (Figure 2). Enzymes involved in this turnover process are phospholipase A2, hydrolyzing phosphoglycerides into lysophosphoglycerides and NEFA like arachidonic acid. The first step in the resynthesis of phosphoglycerides is accomplished by reesterification of arachidonic acid with CoASH. This step, catalyzed by acylCoA synthetase, is ATP dependent. Arachidonoyl CoA reacts with lysophosphoglyceride to yield a new phosphoglyceride molecule. The latter reaction is catalyzed by lysophosphoglyceride acyltransferase.
The Modification of Histidine Residues
Published in Roger L. Lundblad, Chemical Reagents for Protein Modification, 2020
Kinnunen and co-workers44 have been able to differentiate subtypes of acyl-CoA:cholesterol acyltransferase by reactivity with diethylpyrocarbonate (DEP). The liver enzyme (DEP-resistant) had an apparent Ki of 1500 μM while the aortic enzyme (DEP-sensitive) had a Ki of 40 μM.
Nature, Function, and Biosynthesis of Surfactant Lipids
Published in Jacques R. Bourbon, Pulmonary Surfactant: Biochemical, Functional, Regulatory, and Clinical Concepts, 2019
The problem of a role of lamellar bodies in PC remodeling is more complex. Engle et al.59 found a significant lysoPC-palmitoyltransferase activity in a lamellar body-enriched fraction, somewhat higher than that in the microsomal fraction. Using the same approach as for choline phosphotransferase, Barańska and van Golde233 came to the conclusion that lamellar bodies contain neither lysoPC acyltransferase nor lysoPC:lysoPC acyltransferase. However, intriguingly, they observed a stimulation of microsomal acyltransferase activity by the addition of lamellar bodies. This cooperation may explain the previous observation229 of this activity in lamellar bodies which could not simply be accounted for by microsomal contamination. The authors suggested that the presence of lysosomal-type phospholipases in lamellar bodies141 might explain the cooperative effect. Since these lysosomal-type phospholipases appear to preferentially hydrolyze unsaturated PC,139 participation of lamellar bodies in the enrichment of surfactant with DSPC, even if indirect, cannot be ruled out. An alternative explanation involving a particular remodeling system by direct acyl exchange between palmitoyl-CoA and PC has also been hypothesized.59
Emerging clinical investigational drugs for the treatment of amyotrophic lateral sclerosis
Published in Expert Opinion on Investigational Drugs, 2023
Loreto Martinez-Gonzalez, Ana Martinez
(NCT04788745) helps to maintain the energy metabolism of heart muscle cells, protecting them from the effects of reduced oxygen supply and it is used to prevent and treat angina (chest pain). Trimetazidine improves glucose metabolism, enhances mitochondrial metabolism, and promotes nerve regeneration, exerting an anti-inflammatory and antioxidant effect. It is able to inhibit acetyl-coenzyme A acyltransferase 2, an enzyme that catalyses the oxidation of long‐chain fatty acids [76]. Orally administrated to SOD1G93A mice significantly extends overall survival, delays motor function decline, improves muscle performance, prevents the degeneration of neuromuscular junctions, and reduces neuroinflammation in the spinal cord and in peripheral nerves [77]. The phase II study named MetFlex is ongoing with the goal to obtain a stable baseline measurement of clinical markers of disease and oxidative stress. Level of expression of oxidative stress markers in the plasma and/or serum of the 36 ALS patients recruited will be determined as the main outcome together with changes in the ALSFRS-R scores.
Logistic role of carnitine shuttle system on radiation-induced L-carnitine and acylcarnitines alteration
Published in International Journal of Radiation Biology, 2022
Acylcarnitines represent a ‘dormant’ pool of acyl groups that may be used in biochemical pathways upon their conversion back into acyl-CoA esters by carnitine acyltransferases (Adeva Andany et al. 2017). Acyl groups pool provides activated substrates for many critical metabolic pathways such as tricarboxylic acid cycle (TCA), lipid, and cholesterol synthesis for proteins posttranslational modification and detoxication mechanisms (Niu et al. 2019). In this context, acetylcarnitine (C2) donates acetyl group for histone acetylation to modulate epigenetic properties. Acetyl-L-carnitine can be converted into malonyl-CoA in the cytosol to inhibit the activity of CPT1 and reduce the oxidation of fatty acids, which results in eliminating the adverse reactions caused by the accumulation of acyl-CoA metabolic intermediates in the mitochondria (Casals et al. 2016). The long-chain acylcarnitines, notably palmitoylcarnitine, are related to palmitoylation levels of specific proteins (Chen et al. 2017; Niu et al. 2019; Yao et al. 2019). Palmitoylation of proteins is a pervasive posttranslational modification that regulates the transport, compartmentalization and stability of protein, involved in many biological processes such as apoptosis and proliferation.
Role of co- and post-translational modifications of SFKs in their kinase activation
Published in Journal of Drug Targeting, 2020
Mei-Lian Cai, Meng-Yan Wang, Cong-Hui Zhang, Jun-Xia Wang, Hong Liu, Hong-Wei He, Wu-Li Zhao, Gui-Ming Xia, Rong-Guang Shao
During palmitoylation, a palmitoyl group (derived from palmitic acid) is post-translationally added to the cysteine, with less added to serine and threonine. This modification is a dynamic and reversible process. Acyltransferases (PATs) mediate the process. Although myristoylation is essential to membrane anchorage of SFKs [32], myristoylation alone is not sufficient for membrane anchorage, and membrane anchorage still requires other modifications such as palmitoylation (in most SFKs) or a polybasic cluster (in Src) to finish collaboratively [41,42], and the effect of palmitoylation as a second signal to membrane anchorage is stronger than the polybasic cluster [43]. Of note, myristoylation is a prerequisite for the palmitoylation of SFKs. With the exception of Src and Blk, all SFKs are palmitoylated at Cys3, Cys5 or Cys6 in the SH4 domain [32,44]. Lyn and Yes are mono-palmitoylated at Cys3, Fyn is dual-palmitoylated at Cys3 and Cys6, and Lck is dual-palmitoylated at Cys3 and Cys5. Palmitoylation at cysteine affects SFKs activity by regulating the trafficking, localisation and stability of SFKs [45,46].