One-carbon metabolism in cancer

Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism

Specificity of Transmembrane Protein Palmitoylation in Yeast

Many proteins are modified after their synthesis, by the addition of a lipid molecule to one or more cysteine residues, through a thioester bond. This modification is called S-acylation, and more commonly palmitoylation. This reaction is carried out by a family of enzymes, called palmitoyltransferases (PATs), characterized by the presence of a conserved 50- aminoacids domain called “Asp-His-His-Cys- Cysteine Rich Domain” (DHHC-CRD). There are 7 members of this family in the yeast Saccharomyces cerevisiae, and each of these proteins is thought to be responsible for the palmitoylation of a subset of substrates. Substrate specificity of PATs, however, is not yet fully understood. Several yeast PATs seem to have overlapping specificity, and it has been proposed that the machinery responsible for palmitoylating peripheral membrane proteins in mammalian cells, lacks specificity altogether

Targeting N-myristoylation for therapy of B-cell lymphomas

N-myristoyltransferases (NMTs) target many signaling proteins to membranes. Here the authors show an NMT inhibitor named PCLX-001 selectively kills lymphoma cells by shutting down their main survival signaling pathway and offers an additional treatment strategy for lymphoma patients

Palmitoylation Regulates Epidermal Homeostasis and Hair Follicle Differentiation

Palmitoylation is a key post-translational modification mediated by a family of DHHC-containing palmitoyl acyl-transferases (PATs). Unlike other lipid modifications, palmitoylation is reversible and thus often regulates dynamic protein interactions. We find that the mouse hair loss mutant, depilated, (dep) is due to a single amino acid deletion in the PAT, Zdhhc21, resulting in protein mislocalization and loss of palmitoylation activity. We examined expression of Zdhhc21 protein in skin and find it restricted to specific hair lineages. Loss of Zdhhc21 function results in delayed hair shaft differentiation, at the site of expression of the gene, but also leads to hyperplasia of the interfollicular epidermis (IFE) and sebaceous glands, distant from the expression site. The specific delay in follicle differentiation is associated with attenuated anagen propagation and is reflected by decreased levels of Lef1, nuclear β-catenin, and Foxn1 in hair shaft progenitors. In the thickened basal compartment of mutant IFE, phospho-ERK and cell proliferation are increased, suggesting increased signaling through EGFR or integrin-related receptors, with a parallel reduction in expression of the key differentiation factor Gata3. We show that the Src-family kinase, Fyn, involved in keratinocyte differentiation, is a direct palmitoylation target of Zdhhc21 and is mislocalized in mutant follicles. This study is the first to demonstrate a key role for palmitoylation in regulating developmental signals in mammalian tissue homeostasis

The effect of two β-alanine dosing strategies on 30-minute rowing performance: a randomized, controlled trial

Background: β-alanine (βA) supplementation has been shown to increase intramuscular carnosine content and subsequent high-intensity performance in events lasting <4 minutes, which may be dependent on total, as opposed to daily, dose. The ergogenic effect of βA has also been demonstrated for 2000-m rowing performance prompting interest in whether βA may be beneficial for sustained aerobic exercise. This study therefore investigated the effect of two βA dosing strategies on 30-minute rowing and subsequent sprint performance. Methods: Following University Ethics approval, twenty-seven healthy, male rowers (age: 24±2 years; body-height: 1.81±0.02m; body-mass: 82.3±2.5kg; body-fat: 14.2±1.0%) were randomised in a double-blind manner to 4 weeks of: i) βA (2.4 g·d-1, βA1); ii) matched total βA (4.8g on alternate days, βA2); or iii) cornflour placebo (2.4 g·d-1, PL). Participants completed a laboratory 30-minute rowing time-trial, followed by 3x30s maximal sprint efforts at days 0, 14 and 28 (T1-T3). Total distance (m), average power (W), relative average power (W·kg-1), cardio-respiratory measures and perceived exertion were assessed for each 10-minute split. Blood lactate ([La-]b mmol·L-1) was monitored pre-post time-trial and following maximal sprint efforts. A 3-way repeated measures ANOVA was employed for main analyses, with Bonferonni post-hoc assessment (P≤0.05). Results: Total 30-minute time-trial distance significantly increased from T1-T3 within βA1 only (7397±195m to 7580±171m, P=0.002, ƞp2 = 0.196), including absolute average power (194.8±18.3W to 204.2±15.5W, P=0.04, ƞp2=0.115) and relative average power output (2.28±0.15W·kg-1 to 2.41±0.12W·kg-1, P=0.031, ƞp2= 0.122). These findings were potentially explained by within-group significance for the same variables for the first 10 minute split (P≤0.01), and for distance covered (P=0.01) in the second 10-minute split. However, no condition x time interactions were observed. No significant effects were found for sprint variables (P>0.05) with comparable values at T3 for mean distance (βA1: 163.9±3.8m; βA2: 161.2±3.5m; PL: 162.7±3.6m), average power (βA1: 352.7±14.5W; βA2: 342.2±13.5W; PL: 348.2±13.9W) and lactate (βA1: 10.0±0.9mmol·L-1; βA2: 9.2±1.1mmol·L-1; PL: 8.7±0.9mmol·L-1). Conclusions: Whilst daily βA may confer individual benefits, these results demonstrate limited impact of βA (irrespective of dosing strategy) on 30-minute rowing or subsequent sprint performance. Further investigation of βA dosage > 2.4 g·d-1 and/or chronic intervention periods (>4-8 weeks) may be warranted based on within-group observations