Biosynthetic and Regulatory Mechanism of Amino Acids: Regulatory Mechanism of Key Enzymes and the Evolution of Amino Acid Biosynthetic Pathways

2020 ◽  
Vol 58 (4) ◽  
pp. 240-247
Author(s):  
Ayako YOSHIDA
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Regulatory Mechanism ◽  
Biosynthetic Pathways ◽  
Key Enzymes

scholarly journals The Prodomain of Ssy5 Protease Controls Receptor-Activated Proteolysis of Transcription Factor Stp1

2010 ◽  
Vol 30 (13) ◽  
pp. 3299-3309 ◽  
Author(s):  
Thorsten Pfirrmann ◽  
Stijn Heessen ◽  
Deike J. Omnus ◽  
Claes Andréasson ◽  
Per O. Ljungdahl
Keyword(s):  
Amino Acids ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Amino Acid ◽  
Signaling Pathway ◽  
Temperature Control ◽  
Regulatory Mechanism ◽  
Potent Inhibitor ◽  
Large N

ABSTRACT Extracellular amino acids induce the yeast SPS sensor to endoproteolytically cleave transcription factors Stp1 and Stp2 in a process termed receptor-activated proteolysis (RAP). Ssy5, the activating endoprotease, is synthesized with a large N-terminal prodomain and a C-terminal chymotrypsin-like catalytic (Cat) domain. During biogenesis, Ssy5 cleaves itself and the prodomain and Cat domain remain associated, forming an inactive primed protease. Here we show that the prodomain is a potent inhibitor of Cat domain activity and that its inactivation is a requisite for RAP. Accordingly, amino acid-induced signals trigger proteasome-dependent degradation of the prodomain. A mutation that stabilizes the prodomain prevents Stp1 processing, whereas destabilizing mutations lead to constitutive RAP-independent Stp1 processing. We fused a conditional degron to the prodomain to synthetically reprogram the amino acid-responsive SPS signaling pathway, placing it under temperature control. Our results define a regulatory mechanism that is novel for eukaryotic proteases functioning within cells.

Cystathionine β-lyase is involved in d-amino acid metabolism

2018 ◽  
Vol 475 (8) ◽  
pp. 1397-1410 ◽  
Author(s):  
Tetsuya Miyamoto ◽  
Masumi Katane ◽  
Yasuaki Saitoh ◽  
Masae Sekine ◽  
Hiroshi Homma
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Acid Metabolism ◽  
Environmental Changes ◽  
Biosynthetic Pathways ◽  
E Coli ◽  
Comparable Level ◽  
Multifunctional Enzymes ◽  
Dehydratase Activity ◽  
Amino Acid Racemase

Non-canonical d-amino acids play important roles in bacteria including control of peptidoglycan metabolism and biofilm disassembly. Bacteria appear to produce non-canonical d-amino acids to adapt to various environmental changes, and understanding the biosynthetic pathways is important. We identified novel amino acid racemases possessing the ability to produce non-canonical d-amino acids in Escherichia coli and Bacillus subtilis in our previous study, whereas the biosynthetic pathways of these d-amino acids still remain unclear. In the present study, we demonstrated that two cystathionine β-lyases (MetC and MalY) from E. coli produce non-canonical d-amino acids including non-proteinogenic amino acids. Furthermore, MetC displayed d- and l-serine (Ser) dehydratase activity. We characterised amino acid racemase, Ser dehydratase and cysteine lyase activities, and all were higher for MetC. Interestingly, all three activities were at a comparable level for MetC, although optimal conditions for each reaction were distinct. These results indicate that MetC and MalY are multifunctional enzymes involved in l-methionine metabolism and the production of d-amino acids, as well as d- and l-Ser metabolism. To our knowledge, this is the first evidence that cystathionine β-lyase is a multifunctional enzyme with three different activities.

scholarly journals Targeting the Proline–Glutamine–Asparagine–Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy

2021 ◽  
Vol 14 (1) ◽  
pp. 72
Author(s):  
Macus Kuo ◽  
Helen Chen ◽  
Lynn Feun ◽  
Niramol Savaraj
Keyword(s):  
Amino Acids ◽  
Drug Resistance ◽  
Amino Acid ◽  
Lymphoblastic Leukemia ◽  
Essential Amino Acids ◽  
Amino Acid Starvation ◽  
Preclinical Development ◽  
Key Enzymes ◽  
Survival Pathways ◽  
Translational Mechanisms

Proline, glutamine, asparagine, and arginine are conditionally non-essential amino acids that can be produced in our body. However, they are essential for the growth of highly proliferative cells such as cancers. Many cancers express reduced levels of these amino acids and thus require import from the environment. Meanwhile, the biosynthesis of these amino acids is inter-connected but can be intervened individually through the inhibition of key enzymes of the biosynthesis of these amino acids, resulting in amino acid starvation and cell death. Amino acid starvation strategies have been in various stages of clinical applications. Targeting asparagine using asparaginase has been approved for treating acute lymphoblastic leukemia. Targeting glutamine and arginine starvations are in various stages of clinical trials, and targeting proline starvation is in preclinical development. The most important obstacle of these therapies is drug resistance, which is mostly due to reactivation of the key enzymes involved in biosynthesis of the targeted amino acids and reprogramming of compensatory survival pathways via transcriptional, epigenetic, and post-translational mechanisms. Here, we review the interactive regulatory mechanisms that control cellular levels of these amino acids for amino acid starvation therapy and how drug resistance is evolved underlying treatment failure.

scholarly journals Retention and Loss of Amino Acid Biosynthetic Pathways Based on Analysis of Whole-Genome Sequences

2006 ◽  
Vol 5 (2) ◽  
pp. 272-276 ◽  
Author(s):  
Samuel H. Payne ◽  
William F. Loomis
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Minimal Medium ◽  
Whole Genome ◽  
Biosynthetic Pathways ◽  
Genome Sequences ◽  
Whole Genomes ◽  
Complete Genomes ◽  
Computational Analyses

ABSTRACT Plants and fungi can synthesize each of the 20 amino acids by using biosynthetic pathways inherited from their bacterial ancestors. However, the ability to synthesize nine amino acids (Phe, Trp, Ile, Leu, Val, Lys, His, Thr, and Met) was lost in a wide variety of eukaryotes that evolved the ability to feed on other organisms. Since the biosynthetic pathways and their respective enzymes are well characterized, orthologs can be recognized in whole genomes to understand when in evolution pathways were lost. The pattern of pathway loss and retention was analyzed in the complete genomes of three early-diverging protist parasites, the amoeba Dictyostelium, and six animals. The nine pathways were lost independently in animals, Dictyostelium, Leishmania, Plasmodium, and Cryptosporidium. Seven additional pathways appear to have been lost in one or another parasite, demonstrating that they are dispensable in a nutrition-rich environment. Our predictions of pathways retained and pathways lost based on computational analyses of whole genomes are validated by minimal-medium studies with mammals, fish, worms, and Dictyostelium. The apparent selective advantages of retaining biosynthetic capabilities for amino acids available in the diet are considered.

scholarly journals Phenotypic and Genotypic Analysis of Amino Acid Auxotrophy in Lactobacillus helveticus CNRZ 32

2007 ◽  
Vol 74 (2) ◽  
pp. 416-423 ◽  
Author(s):  
Jason K. Christiansen ◽  
Joanne E. Hughes ◽  
Dennis L. Welker ◽  
Beatriz T. Rodríguez ◽  
James L. Steele ◽  
...  
Keyword(s):  
Amino Acids ◽  
Lactic Acid ◽  
Amino Acid ◽  
Lactic Acid Bacteria ◽  
Ornithine Decarboxylase ◽  
Lactobacillus Helveticus ◽  
Decarboxylase Activity ◽  
Biosynthetic Pathways ◽  
Ornithine Decarboxylase Activity ◽  
Genotypic Analysis

ABSTRACT The conversion of amino acids into volatile and nonvolatile compounds by lactic acid bacteria in cheese is thought to represent the rate-limiting step in the development of mature flavor and aroma. Because amino acid breakdown by microbes often entails the reversible action of enzymes involved in biosynthetic pathways, our group investigated the genetics of amino acid biosynthesis in Lactobacillus helveticus CNRZ 32, a commercial cheese flavor adjunct that reduces bitterness and intensifies flavor notes. Most lactic acid bacteria are auxotrophic for several amino acids, and L. helveticus CNRZ 32 requires 14 amino acids. The reconstruction of amino acid biosynthetic pathways from a draft-quality genome sequence for L. helveticus CNRZ 32 revealed that amino acid auxotrophy in this species was due primarily to gene absence rather than point mutations, insertions, or small deletions, with good agreement between gene content and phenotypic amino acid requirements. One exception involved the phenotypic requirement for Asp (or Asn), which genome predictions suggested could be alleviated by citrate catabolism. This prediction was confirmed by the growth of L. helveticus CNRZ 32 after the addition of citrate to a chemically defined medium that lacked Asp and Asn. Genome analysis also predicted that L. helveticus CNRZ 32 possessed ornithine decarboxylase activity and would therefore catalyze the conversion of ornithine to putrescine, a volatile biogenic amine. However, experiments to confirm ornithine decarboxylase activity in L. helveticus CNRZ 32 by the use of several methods were unsuccessful, which indicated that this bacterium likely does not contribute to putrescine production in cheese.

scholarly journals Thermostable D-amino acid decarboxylases derived from Thermotoga maritima diaminopimelate decarboxylase

2021 ◽  
Vol 34 ◽  
Author(s):  
Antonija Marjanovic ◽  
Carlos J Ramírez-Palacios ◽  
Marcelo F Masman ◽  
Jeroen Drenth ◽  
Marleen Otzen ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Building Block ◽  
Catalytic Properties ◽  
Thermotoga Maritima ◽  
Aminocaproic Acid ◽  
Biosynthetic Pathways ◽  
Catalytic Activities ◽  
The Common ◽  
Diaminopimelate Decarboxylase

Abstract Diaminopimelate decarboxylases (DAPDCs) are highly selective enzymes that catalyze the common final step in different lysine biosynthetic pathways, i.e. the conversion of meso-diaminopimelate (DAP) to L-lysine. We examined the modification of the substrate specificity of the thermostable decarboxylase from Thermotoga maritima with the aim to introduce activity with 2-aminopimelic acid (2-APA) since its decarboxylation leads to 6-aminocaproic acid (6-ACA), a building block for the synthesis of nylon-6. Structure-based mutagenesis of the distal carboxylate binding site resulted in a set of enzyme variants with new activities toward different D-amino acids. One of the mutants (E315T) had lost most of its activity toward DAP and primarily acted as a 2-APA decarboxylase. We next used computational modeling to explain the observed shift in catalytic activities of the mutants. The results suggest that predictive computational protocols can support the redesign of the catalytic properties of this class of decarboxylating PLP-dependent enzymes.

scholarly journals Amino Acid Biosynthesis in the Halophilic ArchaeonHaloarcula hispanica

1999 ◽  
Vol 181 (10) ◽  
pp. 3226-3237 ◽  
Author(s):  
Michel Hochuli ◽  
Heiko Patzelt ◽  
Dieter Oesterhelt ◽  
Kurt Wüthrich ◽  
Thomas Szyperski
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Correlation Spectroscopy ◽  
Lysine Biosynthesis ◽  
Biosynthetic Pathways ◽  
Acid Biosynthesis ◽  
Isoleucine Biosynthesis ◽  
Extremely Halophilic Archaeon ◽  
Haloarcula Hispanica ◽  
Labeling Pattern

ABSTRACT Biosynthesis of proteinogenic amino acids in the extremely halophilic archaeon Haloarcula hispanica was explored by using biosynthetically directed fractional 13C labeling with a mixture of 90% unlabeled and 10% uniformly13C-labeled glycerol. The resulting13C-labeling patterns in the amino acids were analyzed by two-dimensional 13C,1H correlation spectroscopy. The experimental data provided evidence for a split pathway for isoleucine biosynthesis, with 56% of the total Ile originating from threonine and pyruvate via the threonine pathway and 44% originating from pyruvate and acetyl coenzyme A via the pyruvate pathway. In addition, the diaminopimelate pathway involving diaminopimelate dehydrogenase was shown to lead to lysine biosynthesis and an analysis of the 13C-labeling pattern in tyrosine indicated novel biosynthetic pathways that have so far not been further characterized. For the 17 other proteinogenic amino acids, the data were consistent with data for commonly found biosynthetic pathways. A comparison of our data with the amino acid metabolisms of eucarya and bacteria supports the theory that pathways for synthesis of proteinogenic amino acids were established before ancient cells diverged into archaea, bacteria, and eucarya.

scholarly journals DksA-Dependent Resistance of Salmonella enterica Serovar Typhimurium against the Antimicrobial Activity of Inducible Nitric Oxide Synthase

2012 ◽  
Vol 80 (4) ◽  
pp. 1373-1380 ◽  
Author(s):  
Calvin A. Henard ◽  
Andrés Vázquez-Torres
Keyword(s):  
Nitric Oxide ◽  
Amino Acids ◽  
Amino Acid ◽  
Rna Polymerase ◽  
Amino Acid Biosynthesis ◽  
Biosynthetic Pathways ◽  
Innate Response ◽  
Acid Biosynthesis ◽  
Content Type ◽  
Serovar Typhimurium

ABSTRACTIn coordination with the ppGpp alarmone, the RNA polymerase regulatory protein DksA controls the stringent response of eubacteria, negatively regulating transcription of translational machinery and directly activating amino acid promoters andde novoamino acid biosynthesis. Given the effects of nitric oxide (NO) on amino acid biosynthetic pathways and the intimate relationship of DksA with amino acid synthesis and transport, we tested whether DksA contributes to the resistance ofSalmonellato reactive nitrogen species (RNS). Our studies show that the zinc finger predicted to position DksA in the secondary channel of the RNA polymerase is essential for the resistance ofSalmonella entericaserovar Typhimurium to RNS in a murine model of systemic salmonellosis. Despite exhibiting auxotrophies for various amino acids, ΔdksAmutantSalmonellastrains regain virulence in mice lacking inducible NO synthase (iNOS). DksA is also important for growth of this intracellular pathogen in the presence of NO congeners generated by iNOS during the innate response of murine macrophages. Accordingly,dksAmutantSalmonellastrains are hypersusceptible to chemically generated NO, a phenotype that can be prevented by adding amino acids. The DksA-dependent antinitrosative defenses do not rely on the Hmp flavohemoprotein that detoxifies NO to NO3−and appear to operate independently of the ppGpp alarmone. Our investigations are consistent with a model by which NO produced in the innate response toSalmonellaexerts considerable pressure on amino acid biosynthesis. The cytotoxicity of NO againstSalmonellaamino acid biosynthetic pathways is antagonized in great part by the DksA-dependent regulation of amino acid biosynthesis and transport.

scholarly journals Transport activity–dependent intracellular sorting of the yeast general amino acid permease

2011 ◽  
Vol 22 (11) ◽  
pp. 1919-1929 ◽  
Author(s):  
Natalie E. Cain ◽  
Chris A. Kaiser
Keyword(s):  
Amino Acids ◽  
Plasma Membrane ◽  
Amino Acid ◽  
Regulatory Mechanism ◽  
Transport Activity ◽  
Amino Acid Permease ◽  
Amino Acid Mixtures ◽  
General Amino Acid Permease ◽  
Intracellular Sorting ◽  
Activity Dependent

Intracellular trafficking of the general amino acid permease, Gap1p, of Saccharomyces cerevisiae is regulated by amino acid abundance. When amino acids are scarce Gap1p is sorted to the plasma membrane, whereas when amino acids are abundant Gap1p is sorted from the trans-Golgi through the multivesicular endosome (MVE) and to the vacuole. Here we test the hypothesis that Gap1p itself is the sensor of amino acid abundance by examining the trafficking of Gap1p mutants with altered substrate specificity and transport activity. We show that trafficking of mutant Gap1pA297V, which does not transport basic amino acids, is also not regulated by these amino acids. Furthermore, we have identified a catalytically inactive mutant that does not respond to complex amino acid mixtures and constitutively sorts Gap1p to the plasma membrane. Previously we showed that amino acids govern the propensity of Gap1p to recycle from the MVE to the plasma membrane. Here we propose that in the presence of substrate the steady-state conformation of Gap1p shifts to a state that is unable to be recycled from the MVE. These results indicate a parsimonious regulatory mechanism by which Gap1p senses its transport substrates to set an appropriate level of transporter activity at the cell surface.

Dietary intake of tryptophan tied emotion-related impulsivity in humans

2019 ◽  
pp. 1-8 ◽  
Author(s):  
Florian Javelle ◽  
Descartes Li ◽  
Philipp Zimmer ◽  
Sheri L. Johnson
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Food Intake ◽  
Essential Amino Acid ◽  
Food Habits ◽  
Psychological Disorder ◽  
Serotonin Synthesis ◽  
Amino Acid Tryptophan ◽  
Pass Through ◽  
Three Factor

Abstract. Emotion-related impulsivity, defined as the tendency to say or do things that one later regret during periods of heightened emotion, has been tied to a broad range of psychopathologies. Previous work has suggested that emotion-related impulsivity is tied to an impaired function of the serotonergic system. Central serotonin synthesis relies on the intake of the essential amino acid, tryptophan and its ability to pass through the blood brain barrier. Objective: The aim of this study was to determine the association between emotion-related impulsivity and tryptophan intake. Methods: Undergraduate participants (N = 25, 16 women, 9 men) completed a self-rated measure of impulsivity (Three Factor Impulsivity Index, TFI) and daily logs of their food intake and exercise. These data were coded using the software NutriNote to evaluate intakes of tryptophan, large neutral amino acids, vitamins B6/B12, and exercise. Results: Correlational analyses indicated that higher tryptophan intake was associated with significantly lower scores on two out of three subscales of the TFI, Pervasive Influence of Feelings scores r =  –.502, p < . 010, and (lack-of) Follow-Through scores, r =  –.407, p < . 050. Conclusion: Findings provide further evidence that emotion-related impulsivity is correlated to serotonergic indices, even when considering only food habits. It also suggests the need for more research on whether tryptophan supplements might be beneficial for impulsive persons suffering from a psychological disorder.

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