scholarly journals Regulatory effects of post-translational modifications on zDHHC S-acyltransferases

2020 ◽  
Vol 295 (43) ◽  
pp. 14640-14652
Author(s):  
Filip Zmuda ◽  
Luke H. Chamberlain
Keyword(s):  
Drug Targets ◽  
Acyl Chain ◽  
Fatty Acyl ◽  
Fatty Acyl Chain ◽  
Physiological Importance ◽  
Cellular Processes ◽  
Cell Growth And Differentiation ◽  
Regulatory Effects ◽  
The Stability ◽  
And Function

The human zDHHC S-acyltransferase family comprises 23 enzymes that mediate the S-acylation of a multitude of cellular proteins, including channels, receptors, transporters, signaling molecules, scaffolds, and chaperones. This reversible post-transitional modification (PTM) involves the attachment of a fatty acyl chain, usually derived from palmitoyl-CoA, to specific cysteine residues on target proteins, which affects their stability, localization, and function. These outcomes are essential to control many processes, including synaptic transmission and plasticity, cell growth and differentiation, and infectivity of viruses and other pathogens. Given the physiological importance of S-acylation, it is unsurprising that perturbations in this process, including mutations in ZDHHC genes, have been linked to different neurological pathologies and cancers, and there is growing interest in zDHHC enzymes as novel drug targets. Although zDHHC enzymes control a diverse array of cellular processes and are associated with major disorders, our understanding of these enzymes is surprisingly incomplete, particularly with regard to the regulatory mechanisms controlling these enzymes. However, there is growing evidence highlighting the role of different PTMs in this process. In this review, we discuss how PTMs, including phosphorylation, S-acylation, and ubiquitination, affect the stability, localization, and function of zDHHC enzymes and speculate on possible effects of PTMs that have emerged from larger screening studies. Developing a better understanding of the regulatory effects of PTMs on zDHHC enzymes will provide new insight into the intracellular dynamics of S-acylation and may also highlight novel approaches to modulate S-acylation for clinical gain.

scholarly journals Regulatory effects of fatty acyl-coenzyme A derivatives on phosphate-activated pig brain and kidney glutaminase in vitro

1975 ◽  
Vol 149 (1) ◽  
pp. 83-91 ◽  
Author(s):  
E Kvamme ◽  
I A Torgner
Keyword(s):  
Acyl Chain ◽  
Bromothymol Blue ◽  
Fatty Acyl ◽  
Fatty Acyl Chain ◽  
Pig Brain ◽  
Low Concentrations ◽  
Regulatory Effects ◽  
Acyl Coenzyme A ◽  
Carnitine Derivatives

1. Fatty n-acyl-CoA derivatives in the concentration range 5 μM-0.1mM and with 5-18 fatty acyl carbons have dual effects on phosphate-activated glutaminase from pig brain and kidney. Generally, fatty acyl-CoA derivatives in low concentrations activate the enzyme, but inhibit at higher concentrations; phosphate and citrate potentiate the activation, displaying positive co-operatively, and protect against inactivation. The fatty acyl-CoA derivatives affect glutaminase similarly to Bromothymol Blue, but differently from acetyl-CoA, which activates the enzyme only at very low phosphate or citrate concentrations. 2. Saturated fatty acyl-CoA derivatives, with 5-10 fatty acyl carbons, only activate the enzyme in the concentration range 0-0.1 mM. When the fatty acyl chain is elongated, the fatty acyl-CoA derivatives gradually become more powerful inhibitors of glutaminase at the expense of their activating capacity. In particular, palmitoyl-CoA and stearoyl-CoA are strong inhibitors at concentrations (10 μM) at which the corresponding free fatty acids and fatty acyl-carnitine derivatives have no effect. 3. The unsaturated fatty acyl-CoA derivatives, oleoyl-CoA and linoleoyl-CoA, behave as potent activators in the lower part of the concentration range tested (0-0.05mM), and as inhibitors in the upper part of this range (0.02-0.10mM). Oleic acid and linoleic acid have similar properties, but their activating capacity is less pronounced. 4. Phosphate both prevented and reversed the inhibition, but no restoration of activity was possible once the enzyme became inactivated. 5. By changing the pH from 7.0 to 8.0 the activating capacity of the fatty acyl-CoA derivatives is increased, as is their concentration range for activation. 6. The fatty acyl-CoA derivatives are somewhat more potent activator for brain glutaminase, but otherwise they affect the two enzymes similarly.

Fatty acyl chain structure, orientational order, and the lipid phase transition in Acholeplasma laidlawii B membranes. A review of recent 19F nuclear magnetic resonance studies

1984 ◽  
Vol 62 (11) ◽  
pp. 1134-1150 ◽  
Author(s):  
P. M. Macdonald ◽  
B. D. Sykes ◽  
R. N. McElhaney
Keyword(s):  
Phase Transition ◽  
Fatty Acids ◽  
Nuclear Magnetic Resonance ◽  
Acyl Chain ◽  
Orientational Order ◽  
Membrane Lipid ◽  
Fatty Acyl ◽  
Fatty Acyl Chain ◽  
Lipid Phase ◽  
Lipid Phase Transition

The orientational order parameters of monofluoropalmitic acids biosynthetically incorporated into membranes of Acholeplasma laidlawii B in the presence of a large excess of a variety of structurally diverse fatty acids have been determined via 19F nuclear magnetic resonance (19F NMR) spectroscopy. It is demonstrated that these monofluoropalmitic acids are relatively nonperturbing membrane probes based upon physical (differential scanning calorimetry), biochemical (membrane lipid analysis), and biological (growth studies) criteria. 19F NMR is shown to convey the same qualitative and quantitative picture of membrane lipid order provided by 2H-NMR techniques and to be sensitive to the structural characteristics of the membrane fatty acyl chains, as well as to the lipid phase transition. Representatives of each naturally occurring class of fatty acyl chain structures, including straight-chain saturated, methyl-branched, monounsaturated, and alicyclic-ring-substituted fatty acids, were studied and the 19F-NMR order parameters were correlated with the lipid phase transitions (determined calorimetrically). The lipid phase transition was the prime determinant of overall orientational order regardless of fatty acid structure. Effects upon orientational order attributable to specific structural substituents were discernible, but were secondary to the effects of the lipid phase transition. In the gel state, relative overall order was directly proportional to the temperature of the particular lipid phase transition. Not only the overall order, but also the order profile across the membrane was sensitive to the presence of particular structural substituents. In particular, in the gel state specific fatty acyl structures demonstrated a characteristic disordering effect in the membrane order profile. These various observations can be merged to provide a unified picture of the manner in which fatty acyl chain chemistry modulates the physical state of membrane lipids.

scholarly journals The Role of Ceramide Metabolism and Signaling in the Regulation of Mitophagy and Cancer Therapy

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2475
Author(s):  
Megan Sheridan ◽  
Besim Ogretmen
Keyword(s):  
Cancer Therapy ◽  
Acyl Chain ◽  
Fatty Acyl ◽  
Fatty Acyl Chain ◽  
Cancer Cell Proliferation ◽  
Bioactive Lipids ◽  
Cellular Functions ◽  
Proliferation Response ◽  
Ceramide Synthases

Sphingolipids are bioactive lipids responsible for regulating diverse cellular functions such as proliferation, migration, senescence, and death. These lipids are characterized by a long-chain sphingosine backbone amide-linked to a fatty acyl chain with variable length. The length of the fatty acyl chain is determined by specific ceramide synthases, and this fatty acyl length also determines the sphingolipid’s specialized functions within the cell. One function in particular, the regulation of the selective autophagy of mitochondria, or mitophagy, is closely regulated by ceramide, a key regulatory sphingolipid. Mitophagy alterations have important implications for cancer cell proliferation, response to chemotherapeutics, and mitophagy-mediated cell death. This review will focus on the alterations of ceramide synthases in cancer and sphingolipid regulation of lethal mitophagy, concerning cancer therapy.

Effect of Acylglycerol Composition and Fatty Acyl Chain Length on Lipid Digestion in pH-Stat Digestion Model and SimulatedIn VitroDigestion Model

2015 ◽  
Vol 81 (2) ◽  
pp. C317-C323
Author(s):  
Jin F. Qi ◽  
Cai H. Jia ◽  
Jung A. Shin ◽  
Jeong M. Woo ◽  
Xiang Y. Wang ◽  
...  
Keyword(s):  
Chain Length ◽  
Acyl Chain ◽  
Fatty Acyl ◽  
Fatty Acyl Chain ◽  
Lipid Digestion ◽  
Acyl Chain Length ◽  
Ph Stat

scholarly journals Acyltransferase-mediated selection of the length of the fatty acyl chain and of the acylation site governs activation of bacterial RTX toxins

2020 ◽  
Vol 295 (28) ◽  
pp. 9268-9280 ◽  
Author(s):  
Adriana Osickova ◽  
Humaira Khaliq ◽  
Jiri Masin ◽  
David Jurnecka ◽  
Anna Sukova ◽  
...  
Keyword(s):  
Acyl Chain ◽  
Fatty Acyl ◽  
Biologically Active ◽  
Fatty Acyl Chain ◽  
Acyl Carrier Proteins ◽  
E Coli ◽  
Rtx Toxins ◽  
Wide Range ◽  
Lysine Residues ◽  
Acyl Chains

In a wide range of organisms, from bacteria to humans, numerous proteins have to be posttranslationally acylated to become biologically active. Bacterial repeats in toxin (RTX) cytolysins form a prominent group of proteins that are synthesized as inactive protoxins and undergo posttranslational acylation on ε-amino groups of two internal conserved lysine residues by co-expressed toxin-activating acyltransferases. Here, we investigated how the chemical nature, position, and number of bound acyl chains govern the activities of Bordetella pertussis adenylate cyclase toxin (CyaA), Escherichia coli α-hemolysin (HlyA), and Kingella kingae cytotoxin (RtxA). We found that the three protoxins are acylated in the same E. coli cell background by each of the CyaC, HlyC, and RtxC acyltransferases. We also noted that the acyltransferase selects from the bacterial pool of acyl–acyl carrier proteins (ACPs) an acyl chain of a specific length for covalent linkage to the protoxin. The acyltransferase also selects whether both or only one of two conserved lysine residues of the protoxin will be posttranslationally acylated. Functional assays revealed that RtxA has to be modified by 14-carbon fatty acyl chains to be biologically active, that HlyA remains active also when modified by 16-carbon acyl chains, and that CyaA is activated exclusively by 16-carbon acyl chains. These results suggest that the RTX toxin molecules are structurally adapted to the length of the acyl chains used for modification of their acylated lysine residue in the second, more conserved acylation site.

scholarly journals Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency

2016 ◽  
Vol 113 (21) ◽  
pp. 5928-5933 ◽  
Author(s):  
Stefka D. Spassieva ◽  
Xiaojie Ji ◽  
Ye Liu ◽  
Kenneth Gable ◽  
Jacek Bielawski ◽  
...  
Keyword(s):  
Acyl Chain ◽  
Strong Association ◽  
Ectopic Expression ◽  
Fatty Acyl ◽  
Chemical Diversity ◽  
Fatty Acyl Chain ◽  
Length Variation ◽  
Ceramide Synthase ◽  
Hydrophobic Moiety

Sphingolipids exhibit extreme functional and chemical diversity that is in part determined by their hydrophobic moiety, ceramide. In mammals, the fatty acyl chain length variation of ceramides is determined by six (dihydro)ceramide synthase (CerS) isoforms. Previously, we and others showed that mutations in the major neuron-specific CerS1, which synthesizes 18-carbon fatty acyl (C18) ceramide, cause elevation of long-chain base (LCB) substrates and decrease in C18 ceramide and derivatives in the brain, leading to neurodegeneration in mice and myoclonus epilepsy with dementia in humans. Whether LCB elevation or C18 ceramide reduction leads to neurodegeneration is unclear. Here, we ectopically expressed CerS2, a nonneuronal CerS producing C22–C24 ceramides, in neurons of Cers1-deficient mice. Surprisingly, the Cers1 mutant pathology was almost completely suppressed. Because CerS2 cannot replenish C18 ceramide, the rescue is likely a result of LCB reduction. Consistent with this hypothesis, we found that only LCBs, the substrates common for all of the CerS isoforms, but not ceramides and complex sphingolipids, were restored to the wild-type levels in the Cers2-rescued Cers1 mutant mouse brains. Furthermore, LCBs induced neurite fragmentation in cultured neurons at concentrations corresponding to the elevated levels in the CerS1-deficient brain. The strong association of LCB levels with neuronal survival both in vivo and in vitro suggests high-level accumulation of LCBs is a possible underlying cause of the CerS1 deficiency-induced neuronal death.

Structure of Escherichia coli membranes. Fatty acyl chain order parameters of inner and outer membranes and derived liposomes

Biochemistry ◽  
1980 ◽  
Vol 19 (8) ◽  
pp. 1638-1643 ◽  
Author(s):  
Hans Ulrich Gally ◽  
Gerd Pluschke ◽  
Peter Overath ◽  
Joachim Seelig
Keyword(s):  
Escherichia Coli ◽  
Acyl Chain ◽  
Fatty Acyl ◽  
Order Parameters ◽  
Fatty Acyl Chain ◽  
Outer Membranes ◽  
Chain Order

Optimization of Phosphatidylserine-Modified Titanium Surfaces for Enhanced Osteoblast Response

2006 ◽  
Author(s):  
Neera Satsangi ◽  
Arpan Satsangi ◽  
Joo L. Ong ◽  
Rajiv V. Satsangi
Keyword(s):  
Alkaline Phosphatase ◽  
Protein Production ◽  
Specific Activity ◽  
Acyl Chain ◽  
Fatty Acyl ◽  
Separate Experiment ◽  
Calcium Deposition ◽  
Fatty Acyl Chain ◽  
Acyl Chain Length

This report is part of a continued effort to evaluate the in vitro osteoblast responses on different phospholipid coatings on Titanium (Ti) implant materials. It has been established that, among analogous phopholipids, the Ti surfaces coated with calcium phosphate (CaP) complex of phosphatidylserine induce the best calcium deposition and osteoblast growth and metabolism. This communication describes an effort to optimize the chemical structure of phosphatidylserine at its position−1 and −2, as Ti surface coating relative to enhancement in osteoblast differentiation and growth in culture. Four synthetic phosphatidylserine analogs with varying fatty acyl chain length and unsaturation were converted to CaP complex, coated on Ti discs, and the osteoblast progenitor cells were cultured on them for up to 14 days to study their differentiation, growth and biochemistry as marked by the expression of alkaline phosphatase specific activity and protein production. In a separate experiment, the topography of the glass surface (glass Petri-dishes) coated the analogous phosphatidylserines, after immersion in simulated body fluid, was examined by scanning electron microscopy (SEM). The presence of calcium and phosphate ions in this deposit was also confirmed. The inclusion of unsaturation in fatty acyl chain in phosphatidylserine enhanced the Total protein production (TPP) as well as the alkaline phosphatase (ALP) specific activity.

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