Allostery in bacterial biosynthesis of a lipid vitamin

While humans depend on dietary sources of menaquinone, or vitamin K2, many bacteria can synthesize their own. Because of this discordance, and because the isoprenoid is used in the bacterial electron transport chain, menaquinone biosynthesis is an appealing potential target for new antimicrobials.

In observance of World Tuberculosis Day, Jodie Johnston of the University of Canterbury in New Zealand wrote in ASBMB Today about her team’s discovery of an allosteric site in the M. tuberculosis enzyme MenD that mediates feedback inhibition in menaquinone biosynthesis. Their paper was selected as an Editor’s Pick in the Journal of Biological Chemistry.

How does allergic contact dermatitis arise?

Classically allergens are peptides, presented by the MHC to a T cell receptor. But most of the molecules that cause contact dermatitis are not peptides. One model to explain this phenomenon is that dermatitis-causing chemicals could bind, covalently or not, to peptides that bind to MHCs, then get presented to T cells. But a new study suggests an alternative, MHC-independent route.

In research appearing in Science Immunology, Nicolai and colleagues screened numerous chemicals for contact allergenicity through CD1, a class of proteins that resemble MHCs in structure and function but have more hydrophobic antigen presentation structures. They found that CD1 can present hydrophobic antigens to T cells, and ordinarily presents lipids from the plasma membrane, such as species of PC, PI, DAG and sphingomyelins. A series of crystal structures shows that “bulky industrial lipids” such as farnesol, which is used in cosmetics and perfumes, appear able to displace these self-lipids. The authors observed differences in response to farnesol among donor T cells that might help explain variations in susceptibility to contact dermatitis. You can read the article here. (open access)

Cell-type-specific deficits in sterol metabolism may contribute to recurrent miscarriage

Progesterone produced by placental tissue plays an important role in early pregnancy. As a steroid hormone, progesterone is produced by conversion of cholesterol through a pregnenolone intermediate. In a recent study in the Journal of Lipid Research, Vondra and colleagues detected differences in cholesterol uptake and progesterone synthesis between cells that remain at the surface of the placenta and those that migrate into the endometrium to direct vascular remodeling. Some preliminary evidence suggests that defects in progesterone synthesis in the latter cell type may contribute to recurrent miscarriage. Read the study here.

High-EPA fish oil derivative approved for cardiovascular disease

The Food and Drug administration has approved Vascepa, a medication derived from fish oil, to treat high triglycerides, which are linked to cardiovascular disease.

Whereas fish oil contains a mix of long-chain omega-3 fatty acids, including eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA), Vascepa, manufactured by Amarin Pharmaceuticals, contains only EPA. According to researchers on the drug’s Phase III study, which was published in the New England Journal of Medicine in January, the drug’s extra benefit compared to fish oil may derive from removing DHA, which has been shown to increase LDL cholesterol.

You can read more on the relative benefits of long-chain omega-3 fatty acids in an open-access editorial by Wolf-Hagen Schunck in the Journal of Lipid Research.

Membrane reorganization impedes plant infection

Plant cells linked by membrane bridges called plasmodesmata need to cut off cytoplasmic communication when pathogens are detected to prevent the spread of viral invaders. Huang and colleagues report in PNAS that signaling induced by the plant defense hormone salicylic acid promotes assembly of sterol and sphingolipid-rich nanodomains that constrict or close plasmodesmata. Read more.

A novel mTORC1 activation mechanism: phosphatidic acid

The cell growth regulator mTOR Complex 1, or mTORC1, is activated in two steps that integrate signals from growth factors and the presence of nutrients. Frias et al. report in the Journal of Biological Chemistry that phospholipase D1, which converts phosphatidylcholine to phosphatidic acid, functions as a coincidence detector responsive to the same nutrient and growth factor signals as mTorC1. The authors demonstrate that phosphatidic acid is a necessary, and in some cases sufficient, for acute mTORC1 activation. The finding may inform the development of therapies for cancers with hyperactive mTORC1.

Blocking fatty acid oxidation fails to improve insulin sensitivity

High circulating fatty acid levels are a risk factor for insulin resistance. The substrate competition model hypothesizes that an excess of mitochondrial fatty acid oxidation (FAO) impairs glycolysis, and would suggest that blocking FAO might improve glucose metabolism and by extension insulin tolerance. However, a team of Danish researchers led by Anne-Marie Lundsgaard reports in the Journal of Lipid Research that inhibiting FAO in mice with a small-molecule carnitine palmitoyltransferase inhibitor does not improve insulin sensitivity. To the contrary, treated mice on a high-fat diet showed lower insulin sensitivity, greater glucose production in the liver, and a reduction in brown adipose tissue markers, suggesting that this strategy for treating insulin resistance will not be viable. Read the article here.

Linoleic acid supplementation makes mice a T. gondii host

Good news for cats: until now, Toxoplasma gondii has only ever reproduced in feline hosts. But recent research by researchers at the University of Washington Madison and the USDA determined that this depends on high levels of omega-6 fatty acids in cat guts (alone among mammals, cats lack delta-6 desaturase) and demonstrated that the parasite would reproduce in mice if linoleic acid was added to the diet. Read a charming writeup in The Atlantic.

Past Research Highlights

Lipid metabolism drives cancer resilience

September 2019 | Kao and colleagues report in the Journal of Lipid Research that selective pressure from chemotherapeutic treatment affects sphingolipid metabolism in leukemia cells. Cells that were most resistant to a standard chemotherapeutic regimen also showed altered sphingolipid metabolism, suggesting that drug resistance may depend on mitochondrial adaptation. To learn more about sphingolipid metabolism, read the Journal of Lipid Research’s recent virtual issue on the subject.

Amino acids may have stabilized prebiotic proto-membranes

August 2019 | An enduring question in studies of the origin of life is how the first lipid membrane was assembled, especially given that it probably happened in a salty aqueous solution inhospitable to lipids. New research in the Proceedings of the National Academy of Sciences suggests that prebiotic amino acids  can bind to and stabilize protocellular membranes. Read more. 

Lipoprotein(a): Many strides made, yet there is a long road ahead.

August 2019 | A virtual issue of the Journal of Lipid Research collects research into the pathophysiology of lipoprotein(a). This lipid-binding protein is linked to atherosclerosis and other cardiovascular diseases, but how it’s assembled, secreted and cleared from the blood are still mysterious. Read the issue, assembled by JLR Junior Associate Editor Gissette Reyes-Soffer, to learn more about Lp(a) and what questions remain.

How accumulation of one lipid disrupts turnover of another

July 2019 | One puzzling feature of gangliosidoses is that often, secondary complex lipids will accumulate even in the absence of  mutations to their turnover pathways. A study from the Sandhoff lab at Bonn University, led by Susi Anheuser, sheds light onto the mechanism for secondary accumulation. Lysosomal lipid degradation enzymes’ activity is affected by the surface charge of lysosomal intraluminal vesicles, and primary lipid-turnover disorders can affect that surface charge. The study appears in the Journal of Lipid Research; read a summary in ASBMB Today.

Ceramide desaturase drives insulin resistance 

July 2019 | Researchers led by Scott Summers report in Science that knocking down the ceramide desaturase DES1 in mice on a high-fat diet improves insulin resistance. The enzyme converts dihydroceramide, which has a saturated side chain, to ceramide, which is unsaturated. Read the article here.

Harmonizing lipidomics

May 2019 | Lipid researchers take center stage in a feature in the May issue of ASBMB Today that explores the history of lipidomics and the challenge of establishing reproducible methods and reference measurements to enable discovery and use of lipid biomarkers. Read the article here.

Blocking lipogenesis, blocking zits

May 2019 | Esler and colleagues from Pfizer’s cardiovascular research unit and the University of California show that, unlike model organisms used to study sebum production, humans generate more than 80% of the lipids in this waxy skin secretion through de novo lipogenesis. Sebum production is higher in people with severe acne. By targeting acetyl-CoA carboxylase, or ACC, with an orally available inhibitor, the researchers reduced participants’ sebum excretion by half. The authors propose that ACC may be a promising therapeutic target to combat acne. (Pfizer is also developing an ACC inhibitor to treat nonalcoholic steatohepatosis.) The work appears in Science Translational Medicine.

Lipid transport: all it takes to reprogram neutrophils

April 2019 | Immune dysregulation is an important part of the cancer landscape: better evasion or dampening of immune responses leads to worse clincal outcomes. Veglia et al. report that pathologically activated neutrophils in cancer overexpress fatty acid transport protein 2, or FATP2. The protein, expressed in response to a growth factor, enables the neutrophils to take up more arachidonic acid and produce more prostaglandin. Pharmacological inhibition or genetic deletion of FATP2 in these cells slowed tumor progression in mice. The study appears in Nature.

Bacteria fight back against an antimicrobial fatty acid

April 2019 | One weapon in the skin’s arsenal against invaders is an unsaturated 16-carbon fatty acid called palmitoleic acid. Subramanian et al., investigating a Staphylococcus aureus fatty acid desaturase called OhyA, discovered that the protein is used to detoxify sebum lipids. Read more. 

Systems genetics of mouse lipid metabolism

March 2019 | Researchers using the hybrid mouse diversity panel developed in LRD member Jake Lusis’s lab to understand how lipid dysregulation leads to liver dysfunction found that lipid abundance appears to correlate with certain proteasomal proteins. Read more.

Membrane desaturation linked to Parkinson’s protein aggregation

December 2018 | Working in yeast and cultured neurons, a team of researchers has shown that inhibiting stearoyl-CoA desaturases can reduce toxic aggregation of alpha-synuclein, the lipid-binding protein that accumulates in Parkinson’s disease. Read the work here.

Ancient sterols give lineage clues on an animal fossil  

October 2018 | You’ve heard of paleogenomics, and maybe paleoproteomics; now, researchers from around the world have used mass spectrometric analysis of lipid biomarkers fossilized in an Ediacaran fossil to establish its phylogeny. Their paper appeared in Science in September.

Structure and synthesis of a key tear film lipid

August 2018 | The August cover article of the Journal of Lipid Research features a newly-reported, ultra-long-chain hydroxy fatty acid that occurs naturally in the lipid layer of human tears. Prior experiments in Langmuir troughs have demonstrated that ultra-long-chain lipids, known as OAHFAs, are required to keep the lipid layer optically clear. Hancock and colleagues characterized the 50-carbon lipid, OAHFA 50:2, and developed a synthesis strategy. Read more.

Mysterious enzyme activity traced to a familiar protein

June 2018 | Plasmalogens are unusual phospholipids, characterized by an ether next to an alkene, a group known as a vinyl ester, that links the head group and one fatty acid tail. Degradation of plasmalogens can produce arachidonic acid, an important precursor to the eicosanoid family of signaling molecules; but how plasmalogens are cleaved was unknown.

Researchers in Richard Gross’s lab at Washington University in St. Louis recently found that mitochondrial protein cytochrome C can cleave the vinyl ester. Because the cytochrome’s plasmalogenase activity is activated by oxidative stress, the finding hints at a link between mitochondrial oxidative stress and inflammation in conditions like ischemia and amyloidosis. Read the original JBC article here, or a Research Highlight here.

Ken Hsu and Caroline Franks discuss diacylglycerol kinase work

August 2017 | Ken Hsu, assistant professor of chemistry at the University of Virginia, and Caroline Franks, a graduate student in the Hsu lab, discuss their research on diacylglycerol kinases (DGKs). Franks is the first author on the paper “The Ligand Binding Landscape of Diacylglycerol Kinases.” Read the paper in the journal Cell Chemical Biology.

Kyle Korshavn discusses how bilayer thickness regulates Aβ aggregation

June 2017 | Kyle Korshavn, a postdoctoral researcher in Ayyalusamy Ramamoorthy’s lab at the University of Michigan, was first author on a paper reporting how pathologically thin lipid bilayers affect amyloid-β aggregation and how pathological lipid oxidation may contribute to Aβ cytotoxicity. Read Korshavn’s paper in the Journal of Biological Chemistry. or watch a video of Korshavn talking about his work.

Proteins and lipids — a complicated relationship?

January 2017 | Researchers have been discussing for many years the role of the lipid matrix in regulating the activity and the organization of membrane proteins. A variety of effects have been singled out and studied qualitatively and quantitatively in model systems. However, the applicability of those results to living cells is — in many cases — unsatisfactory. Read the rest of this “Lipid News” article by Eva Sevcsik and Gerhard J. Schütz in ASBMB Today.