Review

Authors: Johanna Kliche, Ylva Ivarsson

Cellular function is based on protein-protein interactions. A large proportion of these interactions involves the binding of short linear motifs (SLiMs) by folded globular domains. These interactions are regulated by post-translational modifications, such as phosphorylation, that create and break motif binding sites or tune the affinity of the interactions. In addition, motif-based interactions are involved in targeting serine/threonine kinases and phosphatases to their substrate and contribute to the specificity of the enzymatic actions regulating which sites are phosphorylated. Here, we review how SLiM-based interactions assist in determining the specificity of serine/threonine kinases and phosphatases, and how phosphorylation, in turn, affects motif-based interactions. We provide examples of SLiM-based interactions that are turned on/off, or are tuned by serine/threonine phosphorylation and exemplify how this affects SLiM-based protein complex formation.

Topics: Binding Sites; Humans; Phosphoric Monoester Hydrolases; Phosphorylation; Protein Interaction Domains and Motifs; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Serine; Substrate Specificity; Threonine

PubMed: 34989786
DOI: 10.1042/BCJ20200714

Authors: André F S Amaral

Topics: Asthma; Carnitine; Ethanolamines; Female; Glycine; Humans; Male; Methylamines; Oxidative Stress; Serine; Sphingosine N-Acyltransferase; Threonine

PubMed: 24679844
DOI: 10.1016/j.jaci.2014.02.010

Review

Authors: Xiangbing Mao, Xiangfang Zeng, Shiyan Qiao...

Threonine is the second or third limiting amino acid in swine or poultry diets. This nutrient plays a critical role in the maintenance of intestinal mucosal integrity and barrier function, which can be indicated by intestinal morphology, mucus production (number of goblet cells), transepithelial permeability, brush border enzyme activity, and growth performance. Dietary threonine restriction may decrease the production of digestive enzymes and increase mucosal paracellular permeability. A large proportion of dietary threonine is utilized for intestinal-mucosal protein synthesis, especially for mucin synthesis, and there is no oxidation of threonine by enterocytes. Because mucin proteins cannot be digested and reused, intestinal mucin secretion is a net loss of threonine from the body. Luminal threonine availability can influence synthesis of intestinal mucins and other proteins. Under pathological conditions, such as ileitis and sepsis, threonine requirement may be increased to maintain intestinal morphology and physiology. Collectively, knowledge about the role of threonine in mucin synthesis is critical for improving gut health under physiological and pathological conditions in animals and humans.

Topics: Humans; Intestinal Mucosa; Threonine

PubMed: 21622125
DOI: 10.2741/e322

Authors: Marc Stierhof, Maksym Myronovskyi, Josef Zapp...

Dereplication and genome mining in LU18118 combined with heterologous expression of selected biosynthetic gene clusters (BGCs) led to the discovery of various threonine-16:0dioic acids named lipothrenins. Lipothrenins consist of the core elements l-Thr, d--Thr, or Dhb, which are linked to hexadecanedioic acid by an amide bond. The main compound lipothrenin A () carries the -hydroxylated d- form of threonine and expresses a siderophore activity. The lipothrenin BGC was analyzed by a series of deletion experiments. As a result, a variety of interesting genes involved in the recruitment and selective activation of linear 16:0dioic acids, amide bond formation, and the epimerization of l-Thr were revealed. Furthermore, a diiron -oxygenase was identified that may be directly involved in the monooxygenation of the amide bond. This is divergent from the usual hydroxamate formation mechanism in siderophores, which involves hydroxylation of the free amine prior to amide bond formation. Siderophore activity was observed for all -hydroxylated lipothrenins by application of the CAS assay method.

Topics: Siderophores; Threonine; Hydroxamic Acids; Amides; Hydroxylation; Multigene Family

PubMed: 37728876
DOI: 10.1021/acs.jnatprod.3c00097

Authors: Qianqian Lu, Xinzhu Zhou, Ruidan Liu...

Chlorella is a dominant species during harmful algal blooms (HABs) worldwide, which bring about great environmental problems and are also a serious threat to drinking water safety. Application of bacterial algicides is a promising way to control HABs. However, the identified bacterial algicides against Chlorella and the understanding of their effects on algal metabolism are very limited. Here, we isolated a novel bacterium Microbacterium paraoxydans strain M1 that has significant algicidal activities against Chlorella vulgaris (algicidal rate 64.38 %, at 120 h). Atrazine-desethyl (AD) was then identified from strain M1 as an effective bacterial algicide, with inhibition or algae-lysing concentration values (EC) of 1.64 μg/mL and 1.38 μg/mL, at 72 h and 120 h, respectively. LAD (2 μg/mL AD) or HAD (20 μg/mL AD) causes morphology alteration and ultrastructure damage, chlorophyll a reduction, gene expression regulation (for example, psbA, 0.05 fold at 24 h, 2.97 fold at 72 h, and 0.23 fold of the control in HAD), oxidative stress, lipid oxidation (MDA, 2.09 and 3.08 fold of the control in LAD and HAD, respectively, at 120 h) and DNA damage (average percentage of tail DNA 6.23 % at 120 h in HAD, slight damage: 5∼20 %) in the algal cells. The impacts of AD on algal metabolites and metabolic pathways, as well as the algal response to the adverse effects were investigated. The results revealed that amino acids, amines, glycosides and urea decreased significantly compared to the control after 24 h exposure to AD (p < 0.05). The main up-regulated metabolic pathways implied metabonomic resistance and defense against osmotic pressure, oxidative stress, photosynthesis inhibition or partial cellular structure damage, such as phenylalanine metabolism, arginine biosynthesis. The down-regulated glycine, serine and threonine metabolism is a major lead in the algicidal mechanism according to the value of pathway impact. The down-regulated glycine, and serine are responsible for the downregulation of glyoxylate and dicarboxylate metabolism, aminoacyl-tRNA biosynthesis, glutathione metabolism, and sulfur metabolism, which strengthen the algae-lysing effect. It is the first time to highlight the pivotal role of glycine, serine and threonine metabolism in algicidal activities, which provided a new perspective for understanding the mechanism of bacterial algicides exerting on algal cells at the metabolic level.

Topics: Chlorella vulgaris; Chlorophyll A; Herbicides; Harmful Algal Bloom; Photosynthesis; Bacteria; Glycine; Serine; Threonine

PubMed: 38321670
DOI: 10.1016/j.ecoenv.2022.114451

Review

Authors: Martin Heidemann, Dirk Eick

Eukaryotic RNA polymerase II (RNAP II) has evolved an array of heptad repeats with the consensus sequence Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7 at the carboxy-terminal domain (CTD) of its largest subunit (Rpb1). Dynamic phosphorylation of Ser2, Ser5 and Ser7 residues orchestrates the binding of transcription and RNA processing factors to the transcription machinery. Recent studies show that the two remaining potential phosphorylation sites, tyrosine-1 and threonine-4, are phosphorylated as well and contribute to the previously proposed "CTD code". With the impairment of binding of CTD interacting factors, these novel phosphorylation marks add an accessory layer of regulation to the RNAP II transcription cycle.

Topics: Animals; Humans; Phosphorylation; Protein Structure, Tertiary; RNA Polymerase II; Repetitive Sequences, Amino Acid; Threonine; Transcription, Genetic; Tyrosine

PubMed: 22960391
DOI: 10.4161/rna.21726

Authors: Xiaoli Ping, Jeremy M Stark

O-Linked β-N-acetylglucosamine glycosylation (O-GlcNAcylation) to serine or threonine residues is a reversible and dynamic post-translational modification. O-GlcNAc transferase (OGT) is the only enzyme for O-GlcNAcylation, and is a potential cancer therapeutic target in combination with clastogenic (i.e., chromosomal breaking) therapeutics. Thus, we sought to examine the influence of O-GlcNAcylation on chromosomal break repair. Using a set of DNA double strand break (DSB) reporter assays, we found that the depletion of OGT, and its inhibition with a small molecule each caused a reduction in repair pathways that involve use of homology: RAD51-dependent homology-directed repair (HDR), and single strand annealing. In contrast, such OGT disruption did not obviously affect chromosomal break end joining, and furthermore caused an increase in homology-directed gene targeting. Such disruption in OGT also caused a reduction in clonogenic survival, as well as modifications to cell cycle profiles, particularly an increase in G1-phase cells. We also examined intermediate steps of HDR, finding no obvious effects on an assay for DSB end resection, nor for RAD51 recruitment into ionizing radiation induced foci (IRIF) in proliferating cells. However, we also found that the influence of OGT on HDR and homology-directed gene targeting were dependent on RAD52, and that OGT is important for RAD52 IRIF in proliferating cells. Thus, we suggest that OGT is important for regulation of HDR that is partially linked to RAD52 function.

Topics: Acetylglucosamine; Chromosome Breakage; DNA; Humans; N-Acetylglucosaminyltransferases; Serine; Threonine

PubMed: 36095925
DOI: 10.1016/j.dnarep.2022.103394

Authors: Yong Jiang, Ming Xie, Jing Tang...

The present study was conducted to investigate the effects of genetic selection and threonine levels on meat quality in Pekin ducks. At 15 D of age, 192 lean ducks and 192 fatty ducks were selected and allotted to one of three treatments with 8 replicates with similar BW (8 ducks/cage), respectively. All ducks were fed the experimental diets (0.00, 0.15, and 0.30% added threonine) for 21 D from 15 to 35 D of age. The results showed that fatty ducks had higher (P < 0.001) feed intake, feed/gain ratio, abdominal fat percentage, and sebum percentage and lower (P = 0.001) breast muscle percentage compared with that of lean ducks. The fatty-type and lean-type ducks had similar weight gain and BW. Dietary threonine supplementation improved (P < 0.05) growth performance and increased breast muscle percentage in lean-type ducks, but it did not affect (P > 0.05) those indices in fatty-type ducks. Lean ducks had higher (P < 0.001) hepatic contents of total lipids, triglyceride, cholesterol, and plasma low-density lipoprotein cholesterol concentration, and dietary threonine supplementation decreased (P < 0.05) hepatic total lipid, cholesterol, and triglyceride contents in lean ducks, but it had no influence on hepatic lipids in fatty ducks (P > 0.05). Lean ducks had higher (P < 0.05) concentrations of monounsaturated fatty acid (MUFA), and C18-polyunsaturated fatty acid (PUFA) in the liver, PUFA in the breast muscle, and C18:3n6 and C18:3n3 in plasma and lower C20-PUFA and C22-PUFA in the liver and MUFA in plasma, compared with fatty ducks. Threonine supplementation increased PUFA, N3-PUFA, and n6-PUFA in plasma and hepatic fatty acids profiles in lean ducks (P > 0.05) but had on influence on total MUFA and total PUFA in the liver, breast muscle, and plasma in fatty ducks (P > 0.05). In conclusion, genetic selection toward meat production and threonine supplementation increases meat production and PUFA contents, which would influence eating quality, but it is benefit for human health.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Diet; Dietary Supplements; Dose-Response Relationship, Drug; Ducks; Lipids; Liver; Meat; Pectoralis Muscles; Plasma; Random Allocation; Selection, Genetic; Threonine

PubMed: 32359587
DOI: 10.1016/j.psj.2019.10.059

Authors: Noah Nathan Kochen, Vivek Vasandani, Darren Seaney...

Recent high-resolution structures of alpha-synuclein (aSyn) fibrils offer promise for rational approaches to drug discovery for Parkinson's disease and Lewy body dementia. Harnessing the first such structures, we previously used molecular dynamics and free energy calculations to suggest that threonines 72 and 75─which line water-filled cavities within the fibril stacks─may be of central importance in stabilizing fibrils. Here, we used experimental mutagenesis of both wild-type and A53T aSyn to show that both threonine residues play important but surprisingly disparate roles in fibril nucleation and elongation. The T72A mutant, but not T75A, resulted in a large increase in the extent of fibrillization during primary nucleation, leading us to posit that T72 acts as a "brake" on run-away aggregation. An expanded set of simulations of five recent high-resolution fibril structures suggests that confinement of cavity waters around T72 correlates with this finding. In contrast, the T75A mutation led to a modest decrease in the extent of fibrillization. Furthermore, both T72A and T75A completely blocked the initial fibril elongation in seeded fibrillization. To test whether these threonine-lined cavities are druggable targets, we used computational docking to identify potential small-molecule binders. We show that the top-scoring hit, aprepitant, strongly promotes fibril growth while specifically interacting with aSyn fibrils and not monomer, and we offer speculation as to how such compounds could be used therapeutically.

Topics: Humans; Lewy Body Disease; Mutation; Parkinson Disease; Threonine; alpha-Synuclein

PubMed: 36001084
DOI: 10.1021/acschemneuro.2c00327

Authors: Mayke Bezerra Alencar, Richard Marcel Bruno Moreira Girard, Marcell Crispim...

l-Serine and l-threonine have versatile roles in metabolism. In addition to their use in protein synthesis, these amino acids participate in the biosynthesis pathways of other amino acids and even phospholipids. Furthermore, l-serine and l-threonine can be substrates for a serine/threonine dehydratase (Ser/ThrDH), resulting in pyruvate and 2-oxobutyrate, respectively, thus being amino acids with anaplerotic potential. , the etiological agent of Chagas disease, uses amino acids in several biological processes: metacyclogenesis, infection, resistance to nutritional and oxidative stress, osmotic control, etc. This study investigated the import and metabolism of l-serine, l-threonine, and glycine in . Our results demonstrate that these amino acids are transported from the extracellular environment into cells through a saturable transport system that fits the Michaelis-Menten model. Our results show that l-serine and l-threonine can sustain epimastigote cell viability under nutritional stress conditions and stimulate oxygen consumption, maintaining intracellular ATP levels. Additionally, our findings indicate that serine plays a role in establishing the mitochondrial membrane potential in . Serine is also involved in energy metabolism via the serine-pyruvate pathway, which stimulates the production and subsequent excretion of acetate and alanine. Our results demonstrate the importance of l-serine and l-threonine in the energy metabolism of and provide new insights into the metabolic adaptations of this parasite during its life cycle.IMPORTANCE, the parasite responsible for Chagas disease, impacts 5-6 million individuals in the Americas and is rapidly spreading globally due to significant human migration. This parasitic organism undergoes a complex life cycle involving triatomine insects and mammalian hosts, thriving in diverse environments, such as various regions within the insect's digestive tract and mammalian cell cytoplasm. Crucially, its transmission hinges on its adaptive capabilities to varying environments. One of the most challenging environments is the insect's digestive tract, marked by nutrient scarcity between blood meals, redox imbalance, and osmotic stresses induced by the triatomine's metabolism. To endure these conditions, has developed a remarkably versatile metabolic network enabling it to metabolize sugars, lipids, and amino acids efficiently. However, the full extent of metabolites this parasite can thrive on remains incompletely understood. This study reveals that, beyond conventional carbon and energy sources (glucose, palmitic acids, proline, histidine, glutamine, and alanine), three additional metabolites (serine, threonine, and glycine) play vital roles in the parasite's survival during starvation. Remarkably, serine and threonine directly contribute to ATP production through a serine/threonine dehydratase enzyme not previously described in . The significance of this metabolic pathway for the parasite's survival sheds light on how metabolic networks aid in its endurance under extreme conditions and its ability to thrive in diverse metabolic settings.

Topics: Trypanosoma cruzi; Energy Metabolism; Serine; Threonine; Stress, Physiological

PubMed: 40042273
DOI: 10.1128/msphere.00983-24