BACKGROUND: Programmed cell death 1 (PD-1) belongs to immune checkpoint proteins ensuring negative regulation of the immune response. In non-small cell lung cancer (NSCLC), the sensitivity to treatment with anti-PD-1 therapeutics, and its efficacy, mostly correlated with the increase of tumor infiltrating PD-1+ lymphocytes. Due to solid tumor heterogeneity of PD-1+ populations, novel low molecular weight anti-PD-1 high-affinity diagnostic probes can increase the reliability of expression profiling of PD-1+ tumor infiltrating lymphocytes (TILs) in tumor tissue biopsies and in vivo mapping efficiency using immune-PET imaging. METHODS: We designed a 13 kDa β-sheet Myomedin scaffold combinatorial library by randomization of 12 mutable residues, and in combination with ribosome display, we identified anti-PD-1 Myomedin variants (MBA ligands) that specifically bound to human and murine PD-1-transfected HEK293T cells and human SUP-T1 cells spontaneously overexpressing cell surface PD-1. RESULTS: Binding affinity to cell-surface expressed human and murine PD-1 on transfected HEK293T cells was measured by fluorescence with LigandTracer and resulted in the selection of most promising variants MBA066 (hPD-1 KD = 6.9 nM; mPD-1 KD = 40.5 nM), MBA197 (hPD-1 KD = 29.7 nM; mPD-1 KD = 21.4 nM) and MBA414 (hPD-1 KD = 8.6 nM; mPD-1 KD = 2.4 nM). The potential of MBA proteins for imaging of PD-1+ populations in vivo was demonstrated using deferoxamine-conjugated MBA labeled with 68Galium isotope. Radiochemical purity of 68Ga-MBA proteins reached values 94.7-99.3% and in vitro stability in human serum after 120 min was in the range 94.6-98.2%. The distribution of 68Ga-MBA proteins in mice was monitored using whole-body positron emission tomography combined with computerized tomography (PET/CT) imaging up to 90 min post-injection and post mortem examined in 12 mouse organs. The specificity of MBA proteins was proven by co-staining frozen sections of human tonsils and NSCLC tissue biopsies with anti-PD-1 antibody, and demonstrated their potential for mapping PD-1+ populations in solid tumors. CONCLUSIONS: Using directed evolution, we developed a unique set of small binding proteins that can improve PD-1 diagnostics in vitro as well as in vivo using PET/CT imaging.

• Klíčová slova
• Cancer diagnostic, Combinatorial library, Immune checkpoint, Non-small cell lung cancer, Programmed cell death 1, Protein engineering,
• MeSH
• antigeny CD279 * metabolismus   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory plic diagnostické zobrazování   patologie   metabolismus   genetika   MeSH
• nemalobuněčný karcinom plic diagnostické zobrazování   patologie   metabolismus   MeSH
• pozitronová emisní tomografie * metody   MeSH
• proteinové inženýrství * MeSH
• sekvence aminokyselin MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD279 * MeSH
• PDCD1 protein, human MeSH Prohlížeč

BACKGROUND: Siderophores are small iron-binding molecules produced by microorganisms to facilitate iron acquisition from the environment. Radiolabelled siderophores offer a promising solution for infection imaging, as they can specifically target the pathophysiological mechanisms of pathogens. Gallium-68 can replace the iron in siderophores, enabling molecular imaging with positron emission tomography (PET). Stereospecific interactions play a crucial role in the recognition of receptors, transporters, and iron utilisation. Furthermore, these interactions have an impact on the host environment, affecting pharmacokinetics and biodistribution. This study examines the influence of siderophore stereoisomerism on imaging properties, with a focus on ferrirubin (FR) and ferrirhodin (FRH), two cis-trans isomeric siderophores of the ferrichrome type. RESULTS: Tested siderophores were labelled with gallium-68 with high radiochemical purity. The resulting complexes differed in their in vitro characteristics. [68Ga]Ga-FRH showed less hydrophilic properties and higher protein binding values than [68Ga]Ga-FR. The stability studies confirmed the high radiochemical stability of both [68Ga]Ga-siderophores in all examined media. Both siderophores were found to be taken up by S. aureus, K. pneumoniae and P. aeruginosa with similar efficacy. The biodistribution tested in normal mice showed rapid renal clearance with low blood pool retention and fast clearance from examined organs for [68Ga]Ga-FR, whereas [68Ga]Ga-FRH showed moderate retention in blood, resulting in slower pharmacokinetics. PET/CT imaging of mice injected with [68Ga]Ga-FR and [68Ga]Ga-FRH confirmed findings from ex vivo biodistribution studies. In a mouse model of S. aureus myositis, both radiolabeled siderophores showed radiotracer accumulation at the site of infection. CONCLUSIONS: The 68Ga-complexes of stereoisomers ferrirubin and ferrirhodin revealed different pharmacokinetic profiles. In vitro uptake was not affected by isomerism. Both compounds had uptake with the same bacterial culture with similar efficacy. PET/CT imaging showed that the [68Ga]Ga-complexes accumulate at the site of S. aureus infection, highlighting the potential of [68Ga]Ga-FR as a promising tool for infection imaging. In contrast, retention of the radioactivity in the blood was observed for [68Ga]Ga-FRH. In conclusion, the stereoisomerism of potential radiotracers should be considered, as even minor structural differences can influence their pharmacokinetics and, consequently, the results of PET imaging.

• Klíčová slova
• Imaging, Infection, Positron emission tomography, Siderophore, Stereoisomers,
• Publikační typ
• časopisecké články MeSH

Herbal extracts represent a wide spectrum of biologically active ingredients with potential medical applications. By screening minor constituents of jasmine essential oil towards aryl hydrocarbon receptor (AhR) activity using a gene reporter assay (GRA), we found the antagonist effects of jasmone (3-methyl-2-[(2Z)-pent-2-en-1-yl]cyclopent-2-en-1-one). It inhibited 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-, benzo[a]pyrene (BaP)-, and 6-formylindolo[3,2-b]carbazole (FICZ)-triggered AhR-dependent luciferase activity in a concentration-dependent manner. However, the inhibition differed markedly between TCDD, BaP, and FICZ, with the latter being significantly less inhibited. The dose-response analysis confirmed an allosteric type of AhR antagonism. Furthermore, jasmone efficiently inhibited AhR activation by AhR agonists and microbial catabolites of tryptophan (MICTs). TCDD- and FICZ-inducible CYP1A1 expression in primary human hepatocytes was inhibited by jasmone, whereas in the human HepG2 and LS180 cells, jasmone antagonized only TCDD-activated AhR. Jasmone only partially displaced radiolabeled TCDD from its binding to mouse Ahr, suggesting it is not a typical orthosteric ligand of AhR. TCDD-elicited AhR nuclear translocation was not affected by jasmone, whereas downstream signaling events, including the formation of the AhR:ARNT complex and enrichment of the CYP1A1 promoter, were inhibited by jasmone. In conclusion, we show that jasmone is a potent allosteric antagonist of AhR. Such discovery may help to find and/or clarify the use of jasmone in pharmaco- and phytotherapy for conditions where AhR plays a key role.

• Klíčová slova
• AhR, CYP1A1, ChIP, HepG2, LS180, jasmone,
• MeSH
• cytochrom P-450 CYP1A1 genetika   metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• myši MeSH
• polychlorované dibenzodioxiny * škodlivé účinky   MeSH
• receptory aromatických uhlovodíků * antagonisté a inhibitory   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytochrom P-450 CYP1A1 MeSH
• jasmone MeSH Prohlížeč
• ligandy MeSH
• polychlorované dibenzodioxiny * MeSH
• receptory aromatických uhlovodíků * MeSH

The human aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is a pivotal regulator of human physiology and pathophysiology. Allosteric inhibition of AhR was previously thought to be untenable. Here, we identify carvones as noncompetitive, insurmountable antagonists of AhR and characterize the structural and functional consequences of their binding. Carvones do not displace radiolabeled ligands from binding to AhR but instead bind allosterically within the bHLH/PAS-A region of AhR. Carvones do not influence the translocation of ligand-activated AhR into the nucleus but inhibit the heterodimerization of AhR with its canonical partner ARNT and subsequent binding of AhR to the promoter of CYP1A1. As a proof of concept, we demonstrate physiologically relevant Ahr-antagonism by carvones in vivo in female mice. These substances establish the molecular basis for selective targeting of AhR regardless of the type of ligand(s) present and provide opportunities for the treatment of disease processes modified by AhR.

• MeSH
• cytochrom P-450 CYP1A1 genetika   MeSH
• kůže * metabolismus   účinky záření   MeSH
• ligandy MeSH
• myši MeSH
• promotorové oblasti (genetika) MeSH
• receptory aromatických uhlovodíků - jaderný translokátor * genetika   metabolismus   MeSH
• receptory aromatických uhlovodíků * genetika   metabolismus   MeSH
• ultrafialové záření škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytochrom P-450 CYP1A1 MeSH
• ligandy MeSH
• receptory aromatických uhlovodíků - jaderný translokátor * MeSH
• receptory aromatických uhlovodíků * MeSH

Gastrointestinal microbes respond to biochemical metabolites that coordinate their behaviors. Here, we demonstrate that bacterial indole functions as a multifactorial mitigator of Klebsiella grimontii and Klebsiella oxytoca pathogenicity. These closely related microbes produce the enterotoxins tilimycin and tilivalline; cytotoxin-producing strains are the causative agent of antibiotic-associated hemorrhagic colitis and have been associated with necrotizing enterocolitis of premature infants. We demonstrate that carbohydrates induce cytotoxin synthesis while concurrently repressing indole biosynthesis. Conversely, indole represses cytotoxin production. In both cases, the alterations stemmed from differential transcription of npsA and npsB, key genes involved in tilimycin biosynthesis. Indole also enhances conversion of tilimycin to tilivalline, an indole analog with reduced cytotoxicity. In this context, we established that tilivalline, but not tilimycin, is a strong agonist of pregnane X receptor (PXR), a master regulator of xenobiotic detoxification and intestinal inflammation. Tilivalline binding upregulated PXR-responsive detoxifying genes and inhibited tubulin-directed toxicity. Bacterial indole, therefore, acts in a multifunctional manner to mitigate cytotoxicity by Klebsiella spp.: suppression of toxin production, enhanced conversion of tilimycin to tilivalline, and activation of PXR. IMPORTANCE The human gut harbors a complex community of microbes, including several species and strains that could be commensals or pathogens depending on context. The specific environmental conditions under which a resident microbe changes its relationship with a host and adopts pathogenic behaviors, in many cases, remain poorly understood. Here, we describe a novel communication network involving the regulation of K. grimontii and K. oxytoca enterotoxicity. Bacterial indole was identified as a central modulator of these colitogenic microbes by suppressing bacterial toxin (tilimycin) synthesis and converting tilimycin to tilivalline while simultaneously activating a host receptor, PXR, as a means of mitigating tissue cytotoxicity. On the other hand, fermentable carbohydrates were found to inhibit indole biosynthesis and enhance toxin production. This integrated network involving microbial, host, and metabolic factors provides a contextual framework to better understand K. oxytoca complex pathogenicity.

• Klíčová slova
• Klebsiella oxytoca complex, cytotoxin, indole, intestinal inflammation, pregnane X receptor,
• MeSH
• cytotoxiny metabolismus   MeSH
• enterotoxiny metabolismus   MeSH
• indoly metabolismus   MeSH
• infekce bakteriemi rodu Klebsiella * mikrobiologie   MeSH
• Klebsiella oxytoca genetika   metabolismus   MeSH
• lidé MeSH
• novorozenec MeSH
• pseudomembranózní enterokolitida * mikrobiologie   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• cytotoxiny MeSH
• enterotoxiny MeSH
• indoly MeSH

Human gut is in permanent contact with microorganisms that play an important role in many physiological processes including metabolism and immunologic activity. These microorganisms communicate and manage themself by the quorum sensing system (QS) that helps to coordinate optimal growth and subsistence by activating signaling pathways that regulate bacterial gene expression. Diverse QS molecules produced by pathogenic as well as resident microbiota have been found throughout the human gut. However, even a host can by affected by these molecules. Intestinal and immune cells possess a range of molecular targets for QS. Our present knowledge on bacteria-cell communication encompasses G-protein-coupled receptors, nuclear receptors and receptors for bacterial cell-wall components. The QS of commensal bacteria has been approved as a protective factor with favourable effects on intestinal homeostasis and immunity. Signaling molecules of QS interacting with above-mentioned receptors thus parcipitate on maintaining of barrier functions, control of inflammation processes and increase of resistance to pathogen colonization in host organisms. Pathogens QS molecules can have a dual function. Host cells are able to detect the ongoing infection by monitoring the presence and changes in concentrations of QS molecules. Such information can help to set the most effective immune defence to prevent or overcome the infection. Contrary, pathogens QS signals can target the host receptors to deceive the immune system to get the best conditions for growth. However, our knowledge about communication mediated by QS is still limited and detailed understanding of molecular mechanisms of QS signaling is desired.

• Klíčová slova
• G protein-coupled receptors, Indole, N-Acyl-homoserine lactone, Nuclear receptors, Quorum sensing system,
• MeSH
• Bacteria metabolismus   MeSH
• lidé MeSH
• quorum sensing * MeSH
• signální transdukce * MeSH
• střeva parazitologie   MeSH
• střevní mikroflóra * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Microbial metabolite mimicry is a new concept that promises to deliver compounds that have minimal liabilities and enhanced therapeutic effects in a host. In a previous publication, we have shown that microbial metabolites of L-tryptophan, indoles, when chemically altered, yielded potent anti-inflammatory pregnane X Receptor (PXR)-targeting lead compounds, FKK5 and FKK6, targeting intestinal inflammation. Our aim in this study was to further define structure-activity relationships between indole analogs and PXR, we removed the phenyl-sulfonyl group or replaced the pyridyl residue with imidazolopyridyl of FKK6. Our results showed that while removal of the phenyl-sulfonyl group from FKK6 (now called CVK003) shifts agonist activity away from PXR towards the aryl hydrocarbon receptor (AhR), the imidazolopyridyl addition preserves PXR activity in vitro. However, when these compounds are administered to mice, that unlike the parent molecule, FKK6, they exhibit poor induction of PXR target genes in the intestines and the liver. These data suggest that modifications of FKK6 specifically in the pyridyl moiety can result in compounds with weak PXR activity in vivo. These observations are a significant step forward for understanding the structure-activity relationships (SAR) between indole mimics and receptors, PXR and AhR.

• Klíčová slova
• Intestinal inflammation, Microbial mimics, Pregnane X receptor, Tryptophan catabolites,
• MeSH
• adenokarcinom MeSH
• antiflogistika chemie   farmakologie   MeSH
• hepatocyty MeSH
• indoly chemie   farmakologie   MeSH
• játra MeSH
• konformace proteinů MeSH
• lidé středního věku MeSH
• lidé MeSH
• molekulární mimikry MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory tračníku MeSH
• pregnanový X receptor chemie   metabolismus   MeSH
• racionální návrh léčiv MeSH
• střeva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• antiflogistika MeSH
• indoly MeSH
• Nr1i2 protein, mouse MeSH Prohlížeč
• pregnanový X receptor MeSH

The interplays between the metabolic products of intestinal microbiota and the host signaling through xenobiotic receptors, including pregnane X receptor (PXR), are of growing interest, in the context of intestinal health and disease. A distinct class of microbial catabolites is formed from dietary tryptophan, having the indole scaffold in their core structure, which is a biologically active entity. In the current study, we examined a series of ten tryptophan microbial catabolites for their interactions with PXR signaling. Utilizing a reporter gene assay, we identified indole (IND) and indole-3-acetamide (IAD) as PXR agonists. IND and IAD induced PXR-regulated genes CYP3A4 and MDR1 in human intestinal cancer cells. Using time-resolved fluorescence resonance energy transfer, we show that IND (IC50 292 μM) and IAD (IC50 10 μM) are orthosteric ligands of PXR. Binding of PXR in its DNA response elements was enhanced by IND and IAD, as revealed by chromatin immunoprecipitation assay. We demonstrate that tryptophan microbial intestinal metabolites IND and IAD are ligands and agonists of human PXR. These findings are of particular importance in understanding the roles of microbial catabolites in human physiology and pathophysiology. Furthermore, these results are seminal in expanding potential drug repertoire through microbial metabolic mimicry.

• Klíčová slova
• Indole metabolites, Intestinal health, Microbial catabolism, Pregnane X receptor,
• MeSH
• cytochrom P-450 CYP3A genetika   metabolismus   MeSH
• indoly metabolismus   MeSH
• kultivované buňky MeSH
• kyseliny indoloctové metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• nádorové buněčné linie MeSH
• P-glykoproteiny genetika   metabolismus   MeSH
• pregnanový X receptor agonisté   genetika   MeSH
• reportérové geny MeSH
• střevní mikroflóra * MeSH
• střevní sliznice * metabolismus   mikrobiologie   MeSH
• transfekce MeSH
• tryptofan metabolismus   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABCB1 protein, human MeSH Prohlížeč
• CYP3A4 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP3A MeSH
• indole MeSH Prohlížeč
• indoleacetamide MeSH Prohlížeč
• indoly MeSH
• kyseliny indoloctové MeSH
• ligandy MeSH
• P-glykoproteiny MeSH
• pregnanový X receptor MeSH
• tryptofan MeSH

The efforts for therapeutic targeting of the aryl hydrocarbon receptor (AhR) have emerged in recent years. We investigated the effects of available antimigraine triptan drugs, having an indole core in their structure, on AhR signaling in human hepatic and intestinal cells. Activation of AhR in reporter gene assays was observed for Avitriptan and to a lesser extent for Donitriptan, while other triptans were very weak or no activators of AhR. Using competitive binding assay and by homology docking, we identified Avitriptan as a low-affinity ligand of AhR. Avitriptan triggered nuclear translocation of AhR and increased binding of AhR in CYP1A1 promotor DNA, as revealed by immune-fluorescence microscopy and chromatin immune-precipitation assay, respectively. Strong induction of CYP1A1 mRNA was achieved by Avitriptan in wild type but not in AhR-knockout, immortalized human hepatocytes, implying that induction of CYP1A1 is AhR-dependent. Increased levels of CYP1A1 mRNA by Avitriptan were observed in human colon carcinoma cells LS180 but not in primary cultures of human hepatocytes. Collectively, we show that Avitriptan is a weak ligand and activator of human AhR, which induces the expression of CYP1A1 in a cell-type specific manner. Our data warrant the potential off-label therapeutic application of Avitriptan as an AhR-agonist drug.

• Klíčová slova
• Antimigraine drugs, Aryl Hydrocarbon Receptor, Triptans, repurposing,
• MeSH
• aktivace enzymů účinky léků   MeSH
• cytochrom P-450 CYP1A1 genetika   MeSH
• hepatocyty metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• ligandy MeSH
• molekulární modely MeSH
• orgánová specificita MeSH
• přehodnocení terapeutických indikací léčivého přípravku MeSH
• promotorové oblasti (genetika) účinky léků   MeSH
• receptory aromatických uhlovodíků agonisté   chemie   metabolismus   MeSH
• simulace molekulového dockingu MeSH
• střevní sliznice metabolismus   MeSH
• sulfonamidy farmakologie   MeSH
• transkripční faktory bHLH agonisté   chemie   metabolismus   MeSH
• tryptaminy farmakologie   MeSH
• upregulace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• AHR protein, human MeSH Prohlížeč
• avitriptan MeSH Prohlížeč
• CYP1A1 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A1 MeSH
• ligandy MeSH
• receptory aromatických uhlovodíků MeSH
• sulfonamidy MeSH
• transkripční faktory bHLH MeSH
• tryptaminy MeSH

We examined the effects of gut microbial catabolites of tryptophan on the aryl hydrocarbon receptor (AhR). Using a reporter gene assay, we show that all studied catabolites are low-potency agonists of human AhR. The efficacy of catabolites differed substantially, comprising agonists with no or low (i3-propionate, i3-acetate, i3-lactate, i3-aldehyde), medium (i3-ethanol, i3-acrylate, skatole, tryptamine), and high (indole, i3-acetamide, i3-pyruvate) efficacies. We displayed ligand-selective antagonist activities by i3-pyruvate, i3-aldehyde, indole, skatole, and tryptamine. Ligand binding assay identified low affinity (skatole, i3-pyruvate, and i3-acetamide) and very low affinity (i3-acrylate, i3-ethanol, indole) ligands of the murine AhR. Indole, skatole, tryptamine, i3-pyruvate, i3-acrylate, and i3-acetamide induced CYP1A1 mRNA in intestinal LS180 and HT-29 cells, but not in the AhR-knockout HT-29 variant. We observed a similar CYP1A1 induction pattern in primary human hepatocytes. The most AhR-active catabolites (indole, skatole, tryptamine, i3-pyruvate, i3-acrylate, i3-acetamide) elicited nuclear translocation of the AhR, followed by a formation of AhR-ARNT heterodimer and enhanced binding of the AhR to the CYP1A1 gene promoter. Collectively, we comprehensively characterized the interactions of gut microbial tryptophan catabolites with the AhR, which may expand the current understanding of their potential roles in intestinal health and disease.

• Klíčová slova
• aryl hydrocarbon receptor, indoles, microbiome, tryptophan,
• MeSH
• cytochrom P-450 CYP1A1 genetika   MeSH
• exprese genu MeSH
• indoly MeSH
• lidé MeSH
• ligandy MeSH
• metabolické sítě a dráhy MeSH
• multimerizace proteinu MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• promotorové oblasti (genetika) MeSH
• receptory aromatických uhlovodíků agonisté   metabolismus   MeSH
• reportérové geny MeSH
• střevní mikroflóra * účinky léků   MeSH
• transkripční faktory bHLH agonisté   metabolismus   MeSH
• tryptofan metabolismus   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• AHR protein, human MeSH Prohlížeč
• CYP1A1 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A1 MeSH
• indole MeSH Prohlížeč
• indoly MeSH
• ligandy MeSH
• receptory aromatických uhlovodíků MeSH
• transkripční faktory bHLH MeSH
• tryptofan MeSH