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1.
Structural basis of the nonribosomal codes for nonproteinogenic amino acid selective adenylation enzymes in the biosynthesis of natural products.
Kudo, F, Miyanaga, A, Eguchi, T
Journal of industrial microbiology & biotechnology. 2019;(3-4):515-536
Abstract
Nonproteinogenic amino acids are the unique building blocks of nonribosomal peptides (NRPs) and hybrid nonribosomal peptide-polyketides (NRP-PKs) and contribute to their diversity of chemical structures and biological activities. In the biosynthesis of NRPs and NRP-PKs, adenylation enzymes select and activate an amino acid substrate as an aminoacyl adenylate, which reacts with the thiol of the holo form of the carrier protein to afford an aminoacyl thioester as the electrophile for the condensation reaction. Therefore, the substrate specificity of adenylation enzymes is a key determinant of the structure of NRPs and NRP-PKs. Here, we focus on nonproteinogenic amino acid selective adenylation enzymes, because understanding their unique selection mechanisms will lead to accurate functional predictions and protein engineering toward the rational biosynthesis of designed molecules containing amino acids. Based on recent progress in the structural analysis of adenylation enzymes, we discuss the nonribosomal codes of nonproteinogenic amino acid selective adenylation enzymes.
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2.
Proteomic analysis and prediction of amino acid variations that influence protein posttranslational modifications.
Shi, S, Wang, L, Cao, M, Chen, G, Yu, J
Briefings in bioinformatics. 2019;(5):1597-1606
Abstract
Accumulative studies have indicated that amino acid variations through changing the type of residues of the target sites or key flanking residues could directly or indirectly influence protein posttranslational modifications (PTMs) and bring about a detrimental effect on protein function. Computational mutation analysis can greatly narrow down the efforts on experimental work. To increase the utilization of current computational resources, we first provide an overview of computational prediction of amino acid variations that influence protein PTMs and their functional analysis. We also discuss the challenges that are faced while developing novel in silico approaches in the future. The development of better methods for mutation analysis-related protein PTMs will help to facilitate the development of personalized precision medicine.
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3.
Amino and organic acid analysis: Essential tools in the diagnosis of inborn errors of metabolism.
Phipps, WS, Jones, PM, Patel, K
Advances in clinical chemistry. 2019;:59-103
Abstract
Inborn errors of metabolism (IEMs) are a large class of genetic disorders that result from defects in enzymes involved in energy production and metabolism of nutrients. For every metabolic pathway, there are defects that can occur and potentially result in an IEM. While some defects can go undetected in one's lifetime, some have moderate to severe clinical consequences. In the latter case, the biochemical defect leads to accumulation of metabolites and byproducts that are toxic or interfere with normal biological function. Disorders of amino acid metabolism, organic acid metabolism and the urea cycle comprise a large portion of IEMs. Two essential tools required for the diagnosis of these categories of disorders are amino acid and organic acid profiling. Most all clinical laboratories offering metabolic testing perform amino acid analysis, while organic acid profiling is restricted to more specialized pediatric hospitals and reference laboratories. In this chapter, we will provide an overview of various methodologies employed for amino acid and organic acid profiling as well as specific examples to demonstrate how these techniques are applied in clinical laboratories for the diagnosis of IEMs.
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4.
A Pilot Study of Amino Acids in Unresectable Non-Small-Cell Lung Cancer Patients During Chemotherapy: A Randomized Serial N-of-1 Trials Design.
Liu, L, Zhang, Y, Wei, J, Chen, Z, Yu, J
Nutrition and cancer. 2019;(3):399-408
Abstract
The aim of this study was to evaluate the effect of amino acids (AAs) on immune function and inflammation level in patients with NSCLC receiving chemotherapy. We conducted a series of randomized, multiple-crossover, double-blind, placebo-controlled N-of-1 trials comparing AAs with isocaloric glucose in unresectable NSCLC patients and combined the individual results using Bayesian statistical modeling. 25 patients completed two cycles of chemotherapy. The baseline total blood albumin (ALB) level in all patients was 28 ± 3.3 g/l, and the mean total ALB level in patients receiving AAs supplementation and isocaloric glucose was 29.2 ± 2.2 and 28.1 ± 3.7 g/l, respectively (P = 0.028). Patients' baseline C-reactive protein (CRP) level was 4 ± 1.2 mg/l, the mean total CRP level in patients receiving AAs supplementation and isocaloric glucose was 11 ± 2.8 and 13 ± 3.2 mg/l, respectively (P = 0.028). The baseline total blood CD4+ T cells level was 36 ± 7.8%. The percentage of CD4+ T cells in patients receiving AAs supplementation and isocaloric glucose was 42 ± 6.4 and 33.7 ± 17.3, respectively (P = 0.034). Our preliminary results indicated that AAs improve immune status and suppress inflammation in unresectable NSCLC patients receiving chemotherapy.
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5.
Could ornithine supplementation be beneficial to prevent the formation of pro-atherogenic carbamylated low-density lipoprotein (c-LDL) particles?
Simsek, B, Çakatay, U
Medical hypotheses. 2019;:20-22
Abstract
Carbamylation (or carbamoylation) is a non-enzymatic post-translational modification process of lysine residues and protein N-termini, which occurs throughout the lifespan of both various plasma proteins and low-density lipoprotein (LDL) particles. Carbamylation results from the binding of isocyanates spontaneously derived from high levels of blood urea, environmental pollutants, nutritional sources and leads to the formation of potentially atherogenic carbamylated-LDL (c-LDL) particles. The carbamylation of LDL apolipoproteins is associated unfavorable downstream effects. Ornithine is a non-proteinogenic amino acid, which plays a central role at the urea cycle function. The primary use of ornithine in supplements is to support athletic performance, liver function and wound recovery. Ornithine is structurally highly similar to lysine, and is only one carbon atom shorter in its side-chain. Therefore, we hypothesize that supplemented ornithine could compete with ε-amino groups of lysine residues found in apolipoproteins of native LDL particles in their binding to isocyanates and decrease c-LDL formation. This issue still remains unresolved in current literature and needs to be elucidated in experimental studies.
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6.
Diagnostic value of radiolabeled amino acid PET for detection of pseudoprogression of brain tumor after treatment: a meta-analysis.
Kim, SJ, Ryul Shim, S
Nuclear medicine communications. 2019;(9):965-972
Abstract
PURPOSE The purpose of the current study was to investigate the diagnostic performance of radiolabeled amino acid PET for detection of pseudoprogression (PsP) of brain tumor after treatment through a systematic review and meta-analysis. METHODS The PubMed and EMBASE database, from the earliest available date of indexing through 15 February 2019, were searched for studies evaluating the diagnostic performance of radiolabeled amino acid PET for detection of PsP. We determined the sensitivities and specificities across studies, calculated positive and negative likelihood ratios, and constructed summary receiver operating characteristic (SROC) curves. RESULTS Across seven results from six studies (971 patients), the pooled sensitivity was 0.89 [95% confidence interval (CI): 0.82-0.94] without heterogeneity (I2 = 0.0) and a pooled specificity of 0.88 (95% CI: 0.76-0.94) without heterogeneity (I2=29.4). Likelihood ratio syntheses gave an overall positive likelihood ratio of 7.3 (95% CI: 3.6-14.7) and negative likelihood ratio of 0.12 (95% CI: 0.07-0.21). The pooled diagnostic odds ratio (DOR) was 60 (95% CI: 23-152). Hierarchical SROC curve indicates that the areas under the curve (AUC) was 0.92 (95% CI: 0.90-0.94). CONCLUSION The current meta-analysis showed the good sensitivity and specificity of radiolabeled amino acid PET for detection of PsP of brain tumor after treatment. Also, the DOR was high and SROC curve showed high AUC value.
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7.
Study of the metabolomic relationship between lung cancer and chronic obstructive pulmonary disease based on direct infusion mass spectrometry.
Callejón-Leblic, B, Pereira-Vega, A, Vázquez-Gandullo, E, Sánchez-Ramos, JL, Gómez-Ariza, JL, García-Barrera, T
Biochimie. 2019;:111-122
Abstract
The high prevalence of lung cancer (LC) has triggered the search of biomarkers for early diagnosis of this disease. For this purpose the study of metabolic changes related to the development of lung cancer could provide interesting information about its early diagnosis. In this sense, chronic obstructive pulmonary disease (COPD), a disease associated with tumor development, is a comorbidity that increases the risk of onset and progression of lung neoplasia and has also to be considered in the study of pathology related to lung cancer. This work develop a metabolomic approach based on direct infusion mass spectrometry using a hybrid triple quadrupole-time of flight mass spectrometer (DI-ESI-QqQ-TOF-MS) in order to identify altered metabolites from serum of LC and COPD patients and evaluate its relationship and implication in the progression of LC. This methodology has been applied to 30 serum samples from LC, 30 healthy patients used as controls (HC) and 30 serum samples from COPD to found altered metabolites from both LC and COPD diseases. In addition, some metabolic differences and similarities were found in Pulmonary Emphysema and Chronic Bronchitis patients. On the other hand, altered metabolites were studied in different stages of LC (II, III and IV) to evaluate the perturbation of them throughout the progression of disease. The sample treatment consisted of the extraction of polar and non-polar metabolites from serum that was later infused into the mass spectrometer using an electrospray ionization source in positive and negative mode. Partial least squares discriminant analysis (PLS-DA) allowed a classification between LC, HC and COPD groups in all acquisition modes. A total of 35 altered and common metabolites between LC and COPD, including amino acids, fatty acids, lysophospholipids, phospholipids and triacylglycerides were identified, being alanine, aspartate and glutamate metabolism the most altered. Finally, ROC curves were applied to the dataset and metabolites with AUC value higher than 0.70 were considered as relevant in the progression of LC.
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8.
Oxaliplatin-Fluoropyrimidine Combination (XELOX) Therapy Does Not Affect Plasma Amino Acid Levels and Plasma Markers of Oxidative Stress in Colorectal Cancer Surgery Patients: A Pilot Study.
Aquilani, R, Brugnatelli, S, Dossena, M, Maestri, R, Delfanti, S, Buonocore, D, Boschi, F, Simeti, E, Condino, AM, Verri, M
Nutrients. 2019;(11)
Abstract
Chemotherapy for colorectal cancer may lower muscle protein synthesis and increase oxidative stress. We hypothesize that chemotherapy may worsen plasma amino acids (AAs) and markers of oxidative stress (MOS). Therefore, this study aimed to document plasma AAs and MOS before, during and after chemotherapy in colorectal cancer (CRC) surgery patients. Fourteen normal-weight CRC patients were enrolled one month after surgery and scheduled for oxaliplatin-fluoropyrimidine combination (XELOX) therapy. Venous blood samples for AA and MOS (malondialdehyde, MDA; 8-hydroxy-2'-deoxyguanosine, 8-OHdG) measurements were drawn in fasting patients before each oxaliplatin infusion at initiation (A), 1 month (B) and 3 months (C) of the therapy, and after XELOX had finished (6 months, D). The results showed that during XELOX therapy (from phase B to phase D), in comparison to baseline (phase A), the branched chain amino acid/essential amino acid ratio, branched chain amino acids expressed as a percentage of total AAs, and arginine expressed as a percentage of total AAs significantly decreased (p = 0.017, p = 0.028, p = 0.028, respectively). Plasma levels of MOS did not change significantly. This study indicates that XELOX therapy does not affect plasma AA levels or worsen oxidative stress.
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9.
Are dietary amino acids prospectively predicts changes in serum lipid profile?
Teymoori, F, Asghari, G, Salehi, P, Sadeghian, S, Mirmiran, P, Azizi, F
Diabetes & metabolic syndrome. 2019;(3):1837-1843
Abstract
BACKGROUND Besides of dietary fat and carbohydrate, amino acids(AAs), as constituent components of dietary protein have been related with serum lipid levels. This study aims to examine the association between dietary AAs and prospective changes in serum lipid profile in adults. METHODS Analyses were conducted on 3881 participants aged, 18-75 years of Tehran lipid and Glucose study, at baseline (2008-2011) and were followed for 3 years (2011-2014) to ascertain serum lipid profile changes. Dietary intakes of AAs were collected at baseline using food frequency questionnaire. Multiple linear regression adjusted for age, sex, body mass index, physical activity, smoking and daily intakes of energy, total fat, and fiber were used. RESULTS The median(IQR) changes in triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) were 6.0(-19.0, -35.5), 9.0(7.0, -24.0), 1.0(-3.0, -6.0), and 5.2(-8.0, -18.6) mg/dl, respectively. Higher intakes of isoleucine, lysine, tyrosine, alanine, threonine, methionine, valine, histidine, aspartic acid, and branched chain, alkaline, and alcoholic AAs were positively associated with TGs-changes in the final adjusted model, whereas tryptophan, glutamic acid, and acidic AAs were negatively related to TG-changes. Alanine and tryptophan were associated with higher and lower LDL-C-changes, respectively. Lysine, alanine, methionine, aspartic acid, and alkaline AAs showed positive association with changes in TC, whereas tryptophan and glutamic acid had a negative association with TC-changes. CONCLUSION Our findings showed that some dietary amino acids have the potential to increase or decrease serum lipid profile.
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10.
A metric space for semantic containment: Towards the implementation of genetic firewalls.
Schmidt, M
Bio Systems. 2019;:104015
Abstract
Analysing or engineering the genetic code has mainly been considered as an approach to reduce or increase the mutational robustness of the genetic code, i.e. the error tolerance in DNA mutations, or to enable the incorporation of non-canonical amino acids. The approach of "semantic containment", however, is less interested in altering the mutational tolerance of the standard code, but to create synthetic alternative genetic codes that limit or all together impede horizontal gene transfer between a natural and genomically recoded organisms (GRO). A major claim or conjecture of semantic containment is: "the farther, the safer", meaning, the less similarity there is between two codes, the less chance of a horizontal gene transfer, and the stronger the genetic firewall. So far, no metrics were available to measure and quantify the "genetic distance" between different genetic codes. Such a metric, however, is iis paramount to allow the experimental testing and evaluation of the validity of semantic biocontainment for the first time. Here, we introduce a metric space to measure exactly the distance (dissimilarity) between different genetic codes, in order to provide a framework to evaluate the relation between distance and strength of a genetic firewall. Results are presented that incorporate bespoken metrics when producing alternative genetic codes according to predefined goals, specifications and limitations. Finally, as an outlook, implications and challenges for genetic firewall(s) are discussed for dual- and multi-code systems.