scholarly journals Lysine Fatty Acylation: Regulatory Enzymes, Research Tools, and Biological Function

2021 ◽  
Vol 9 ◽  
Author(s):  
Garrison Komaniecki ◽  
Hening Lin
Keyword(s):  
Biological Function ◽  
Fatty Acyl ◽  
Common Mechanism ◽  
Fatty Acylation ◽  
Regulatory Enzymes ◽  
Molecular Context ◽  
Initial Discovery ◽  
Long Chain ◽  
Physiological Outcome

Post-translational acylation of lysine side chains is a common mechanism of protein regulation. Modification by long-chain fatty acyl groups is an understudied form of lysine acylation that has gained increasing attention recently due to the characterization of enzymes that catalyze the addition and removal this modification. In this review we summarize what has been learned about lysine fatty acylation in the approximately 30 years since its initial discovery. We report on what is known about the enzymes that regulate lysine fatty acylation and their physiological functions, including tumorigenesis and bacterial pathogenesis. We also cover the effect of lysine fatty acylation on reported substrates. Generally, lysine fatty acylation increases the affinity of proteins for specific cellular membranes, but the physiological outcome depends greatly on the molecular context. Finally, we will go over the experimental tools that have been used to study lysine fatty acylation. While much has been learned about lysine fatty acylation since its initial discovery, the full scope of its biological function has yet to be realized.

scholarly journals Novel inhibitory action of tunicamycin homologues suggests a role for dynamic protein fatty acylation in growth cone-mediated neurite extension

1994 ◽  
Vol 124 (4) ◽  
pp. 521-536 ◽  
Author(s):  
SI Patterson ◽  
JH Skene
Keyword(s):  
Growth Cone ◽  
Growth Cones ◽  
Fatty Acyl ◽  
Protein Glycosylation ◽  
Neuronal Growth ◽  
Fatty Acylation ◽  
Protein Palmitoylation ◽  
Cone Function ◽  
Neuronal Growth Cones ◽  
Long Chain

In neuronal growth cones, the advancing tips of elongating axons and dendrites, specific protein substrates appear to undergo cycles of posttranslational modification by covalent attachment and removal of long-chain fatty acids. We show here that ongoing fatty acylation can be inhibited selectively by long-chain homologues of the antibiotic tunicamycin, a known inhibitor of N-linked glycosylation. Tunicamycin directly inhibits transfer of palmitate to protein in a cell-free system, indicating that tunicamycin inhibition of protein palmitoylation reflects an action of the drug separate from its previously established effects on glycosylation. Tunicamycin treatment of differentiated PC12 cells or dissociated rat sensory neurons, under conditions in which protein palmitoylation is inhibited, produces a prompt cessation of neurite elongation and induces a collapse of neuronal growth cones. These growth cone responses are rapidly reversed by washout of the antibiotic, even in the absence of protein synthesis, or by addition of serum. Two additional lines of evidence suggest that the effects of tunicamycin on growth cones arise from its ability to inhibit protein long-chain acylation, rather than its previously established effects on protein glycosylation and synthesis. (a) The abilities of different tunicamycin homologues to induce growth cone collapse very systematically with the length of the fatty acyl side-chain of tunicamycin, in a manner predicted and observed for the inhibition of protein palmitoylation. Homologues with fatty acyl moieties shorter than palmitic acid (16 hydrocarbons), including potent inhibitors of glycosylation, are poor inhibitors of growth cone function. (b) The tunicamycin-induced impairment of growth cone function can be reversed by the addition of excess exogenous fatty acid, which reverses the inhibition of protein palmitoylation but has no effect on the inhibition of protein glycosylation. These results suggest an important role for dynamic protein acylation in growth cone-mediated extension of neuronal processes.

Determination and characterization of long-chain fatty acyl-CoA thioesters from yeast and mammalian liver

1981 ◽  
Vol 113 (2) ◽  
pp. 386-397 ◽  
Author(s):  
Alexander Olbrich ◽  
Brigitte Dietl ◽  
Feodor Lynen
Keyword(s):  
Fatty Acyl ◽  
Mammalian Liver ◽  
Coa Thioesters ◽  
Long Chain

scholarly journals Biochemical characterization of the PHARC-associated serine hydrolase ABHD12 reveals its preference for very-long-chain lipids

2018 ◽  
Vol 293 (44) ◽  
pp. 16953-16963 ◽  
Author(s):  
Alaumy Joshi ◽  
Minhaj Shaikh ◽  
Shubham Singh ◽  
Abinaya Rajendran ◽  
Amol Mhetre ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Biochemical Characterization ◽  
Fatty Acyl ◽  
Endoplasmic Reticulum Membrane ◽  
Long Chain Fatty Acids ◽  
Serine Hydrolase ◽  
Brain Membrane ◽  
Chain Lengths ◽  
Long Chain

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is a rare genetic human neurological disorder caused by null mutations to the Abhd12 gene, which encodes the integral membrane serine hydrolase enzyme ABHD12. Although the role that ABHD12 plays in PHARC is understood, the thorough biochemical characterization of ABHD12 is lacking. Here, we report the facile synthesis of mono-1-(fatty)acyl-glycerol lipids of varying chain lengths and unsaturation and use this lipid substrate library to biochemically characterize recombinant mammalian ABHD12. The substrate profiling study for ABHD12 suggested that this enzyme requires glycosylation for optimal activity and that it has a strong preference for very-long-chain lipid substrates. We further validated this substrate profile against brain membrane lysates generated from WT and ABHD12 knockout mice. Finally, using cellular organelle fractionation and immunofluorescence assays, we show that mammalian ABHD12 is enriched on the endoplasmic reticulum membrane, where most of the very-long-chain fatty acids are biosynthesized in cells. Taken together, our findings provide a biochemical explanation for why very-long-chain lipids (such as lysophosphatidylserine lipids) accumulate in the brains of ABHD12 knockout mice, which is a murine model of PHARC.

Targeting IDH Mutations in AML: Wielding the Double-edged Sword of Differentiation

2020 ◽  
Vol 20 (7) ◽  
pp. 490-500 ◽  
Author(s):  
Justin S. Becker ◽  
Amir T. Fathi
Keyword(s):  
Genome Structure ◽  
Cellular Metabolism ◽  
Standard Of Care ◽  
Competitive Inhibitor ◽  
Driver Mutations ◽  
New Class ◽  
Regulatory Enzymes ◽  
Idh Mutations ◽  
Genomic Characterization

The genomic characterization of acute myeloid leukemia (AML) by DNA sequencing has illuminated subclasses of the disease, with distinct driver mutations, that might be responsive to targeted therapies. Approximately 15-23% of AML genomes harbor mutations in one of two isoforms of isocitrate dehydrogenase (IDH1 or IDH2). These enzymes are constitutive mediators of basic cellular metabolism, but their mutated forms in cancer synthesize an abnormal metabolite, 2- hydroxyglutarate, that in turn acts as a competitive inhibitor of multiple gene regulatory enzymes. As a result, leukemic IDH mutations cause changes in genome structure and gene activity, culminating in an arrest of normal myeloid differentiation. These discoveries have motivated the development of a new class of selective small molecules with the ability to inhibit the mutant IDH enzymes while sparing normal cellular metabolism. These agents have shown promising anti-leukemic activity in animal models and early clinical trials, and are now entering Phase 3 study. This review will focus on the growing preclinical and clinical data evaluating IDH inhibitors for the treatment of IDH-mutated AML. These data suggest that inducing cellular differentiation is central to the mechanism of clinical efficacy for IDH inhibitors, while also mediating toxicity for patients who experience IDH Differentiation Syndrome. Ongoing trials are studying the efficacy of IDH inhibitors in combination with other AML therapies, both to evaluate potential synergistic combinations as well as to identify the appropriate place for IDH inhibitors within existing standard-of-care regimens.

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