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Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
Posttranslational modifications such as phosphorylation, glycosylation, and palmitoylation play important roles in the dynamics of the DARs and ultimately determine their efficacy. Several consensus phosphorylation sites, located at the cytoplasmic tail as well as ICL3, are involved in homologous and heterologous desensitization [14]. In addition, glycosylation sites at the N-terminus and ECL1 are important for the maturation and intracellular transport of some of the receptors [15]. In most receptors, the cytoplasmic tail has a site of palmitoylation, i.e., a covalent lipid modification of the side chain of Cys residues with the 16-carbon fatty acid palmitate. Palmitoylation facilitates the anchoring of the receptors to the plasma membrane and plays a role in receptor oligomerization [14].
N-Myristoylation as a Novel Molecular Target for the Design of Chemotherapeutic Drugs
Published in Robert I. Glazer, Developments in Cancer Chemotherapy, 2019
Ronald L. Felsted, Colin Goddard, Constance J. Glover
In contrast, the apparent delay in palmitoylation of from 15 min to several hours suggests that there is a different subcellular location for the enzymes that catalyze palmitate protein acylation. An example is the posttranslational palmitoylation of viral glycoproteins which takes place about 15 min after protein biosynthesis in the vicinity of the transitional elements of the endoplasmic reticulum and the cis-Golgi.42,62,72 Protein acyl transferase(s) capable of catalyzing this reaction have been demonstrated in vitro using microsomal membranes.73 Palmitoylation is also catalyzed by acyl transferase(s) located in the plasma membrane. For example, p21ras and ankyrin are thought to be palmitoylated by plasma membrane acyl transferase(s) just prior to or coincident with membrane binding.30,44 Another example is an acyl protein transferase activity from reticulocyte plasma membranes, which may be responsible for the palmitoylation of the transferrin receptor glycoprotein up to 48 hr after translation.43,74
Micronutrients for Improved Management of Huntington’s Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Post-translational modification of proteins by the lipid palmitate is needed for the correct targeting and functioning of certain proteins, including huntingtin protein. Palmitoylation of proteins is regulated by two functionally opposing enzymes palmitoyl acyltransferases, which add palmitate to proteins, and acyl protein thioesterases, which remove palmitate from proteins. This process of palmitate is important for the development of synapses and synaptic activity in the brain. Wild-type huntingtin protein is palmitoylated by huntingtin-interacting protein-14 (HIP-14), which exhibits palmitate acyltransferase activity.61 If the interaction between HD protein and HIP-14 is reduced, the palmitoylation of HD protein is decreased leading to increased protein aggregations and neuronal toxicity. Conversely, overexpression of HIP-14 can increase palmitoylation and this markedly reduced HD protein aggregation. This study suggests that palmitoylation by HIP-14 plays a role in the pathogenesis of HD. This was further supported by the study in which deletion of HIP-14 caused development of HD pathology and behavioral features in mice.62 Huntingtin-interacting protein-14 like (HIP-14L) is a paralog (as a result of gene duplication that may acquire different function) of HIP-14. Both HIP-14 and HIP-14L are essential for palmitoylation of huntingtin protein. HIP-14L-deficient mice have reduced palmitoylation of the HIP-14L substrate SNAP25 (synaptosomal-associated protein-25), early onset of motor deficits, and widespread and progressive neurodegeneration in the brain.63
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.
Toward the identification of ZDHHC enzymes required for palmitoylation of viral protein as potential drug targets
Published in Expert Opinion on Drug Discovery, 2020
Mohamed Rasheed Gadalla, Michael Veit
Although palmitoylation of viral proteins was already discovered 40 years ago [32], the enzymes catalyzing the reaction were never identified with biochemical fractionation methods, although cell-free assays were developed [36]. Nevertheless, it was quickly established that palmitoylation is a common modification of viral proteins [56]. The possibility to create recombinant virus, finally developed for Influenza virus in 1999 [190], revealed that removing palmitoylation sites often has drastic effects on virus replication, most thoroughly investigated for Influenza virus HA [57]. The discovery that ZDHHCs catalyze acylation of cellular proteins [102,103] and that the 23 family members have only partially overlapping substrate specificities [130] suggested that inhibition of palmitoylation of a viral protein might have little side effects, since a large part of the cellular acylation machinery is not affected. Due to improved screening strategies ZDHHCs for some viral proteins have been identified in the last years. No palmitoylation specific inhibitors have been developed so far, but the recent crystallization of two ZDHHCs will be helpful in this regard [121]. The structures also offered a molecular explanation how a ZDHHC might prefer certain acyl chains over others, which partly explains the site-specific acylation of Influenza virus HA [38].
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
Various palmitoylation states (no, mono and dual) lead to different membrane domain interactions. For instance, palmitoylated SFKs show preferred localisation to raft domains (membrane micro domains) compared to the non-palmitoylated SFKs [50], and the localisation in raft domains of the cell membrane limits cell metastasis. In contrast, the SFKs lacking palmitoylation (e.g. Src) show a weaker affinity for the raft domain in the membrane and are targeted to the non-raft pTyr-protein, helping to activate the signal pathway associated with metastasis and then contributing to metastasis [43]. Palmitoylation may also play important roles in signalling events. A study from Askar M showed that when Fas was activated, the palmitoylation levels of Lck underwent extremely rapid and transient elevation. The loss of Lck palmitoylation impaired Fas-mediated apoptosis. These results demonstrated an essential role for Lck palmitoylation in signalling downstream of the Fas receptor [51].