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Wheat (Triticum aestivum) is a major staple crop worldwide, and its yields are significantly threatened by wheat powdery mildew (Blumeria graminis f. sp. tritici). Enhancing disease resistance in wheat is crucial for meeting global food demand. This study investigated the disease response in wheat, focusing on the bioactive small molecules salicylic acid (SA), pipecolic acid (Pip), and N-hydroxypipecolic acid (NHP), to provide new insights for molecular breeding. We found that endogenous levels of SA, Pip, and NHP significantly increased in infected plants, with Pip and NHP levels rising earlier than those of SA. Notably, the rate of increase of NHP was substantially higher than that of SA. The gene expression levels of SARD1 and CBP60g, which are transcription factors for SA, Pip, and NHP biosynthesis, increased significantly during the early stages of infection. We also found that during the later stages of infection, the expression of ALD1, SARD4, and FMO1, which encode enzymes for Pip and NHP biosynthesis, dramatically increased. Additionally, ICS1, which encodes a key enzyme involved in SA biosynthesis, also showed increased expression during the later stages of infection. The temporal changes in ICS1 transcription closely mirrored the behavior of endogenous SA levels, suggesting that the ICS pathway is the primary route for SA biosynthesis in wheat. In conclusion, our results suggest that the early accumulation of Pip and NHP cooperates with SA in the disease response against wheat powdery mildew infection.

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l-Pipecolic acid (L-PA), an essential chiral cyclic nonprotein amino acid, is gaining prominence in the food and pharmaceutical sectors due to its wide-ranging biological and pharmacological properties. Historically, L-PA has been synthesized chemically for commercial purposes. This study introduces a novel and efficient microbial production method for L-PA using engineered strain Saccharomyces cerevisiae BY4743. Initially, an optimized biosynthetic pathway was constructed within S. cerevisiae, converting glucose to L-PA with a yield of 0.60 g/L in a 250 mL shake flask in vivo. Subsequently, a multifaceted engineering strategy was implemented to enhance L-PA production: substrate-enzyme affinity modification, global transcription machinery engineering modification, and Kozak sequence optimization for enhanced L-PA production. Approaches above led to an impressive 8.6-fold increase in L-PA yield, reaching 5.47 g/L in shake flask cultures. Further scaling up in a 5 L fed-batch fermenter achieved a remarkable L-PA concentration of 74.54 g/L. This research offers innovative insights into the industrial-scale production of L-PA.

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ALDH7A1 deficiency is an epileptic encephalopathy whose seizures respond to treatment with supraphysiological doses of pyridoxine. It arises as a result of damaging variants in ALDH7A1, a gene in the lysine catabolism pathway. α-Aminoadipic semialdehyde (α-AASA) and Δ1-piperideine-6-carboxylate (P6C), which accumulate because of the block in the lysine pathway, are diagnostic biomarkers for this disorder. Recently, it has been reported that 6-oxo-pipecolic acid (6-oxo-PIP) also accumulates in the urine, CSF and plasma of ALDH7A1-deficient individuals and that, given its improved stability, it may be a more suitable biomarker for this disorder. This study measured 6-oxo-PIP in urine from a cohort of 30 patients where α-AASA was elevated and showed that it was above the normal range in all those above 6 months of age. However, 6-oxo-PIP levels were within the normal range in 33% of the patients below 6 months of age. Levels increased with age and correlated with a decrease in α-AASA levels. Longitudinal analysis of urine samples from ALDH7A1-deficient patients who were on a lysine restricted diet whilst receiving supraphysiological doses of pyridoxine showed that levels of 6-oxo-PIP remained elevated whilst α-AASA decreased. Similar to α-AASA, we found that elevated urinary excretion of 6-oxo-PIP can also occur in individuals with molybdenum cofactor deficiency. This study demonstrates that urinary 6-oxo-PIP may not be a suitable biomarker for ALDH7A1 deficiency in neonates. However, further studies are needed to understand the biochemistry leading to its accumulation and its potential long-term side effects.

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The disturbed gut microbiota is a key factor in activating the aflatoxin B1 (AFB1)-induced liver pyroptosis by promoting inflammatory hepatic injury; however, the pathogen associated molecular pattern (PAMP) from disturbed gut microbiota and its mechanism in activating liver pyroptosis remain undefined. By transplanting AFB1-originated fecal microbiota and sterile fecal microbial metabolites filtrate, we determined the association of PAMP in AFB1-induced liver pyroptosis. Notably, AFB1-originated sterile fecal microbial metabolites filtrate were more active in triggering liver pyroptosis in mice, as compared to parental fecal microbiota. This result supported a critical role of the metabolic homeostasis of gut microbiota in AFB1-induced liver pyroptosis, rather than an injurious response to direct exposure of AFB1 in liver. Among the gut-microbial metabolites, pipecolic acid and norepinephrine were proposed to bind TLR4 and NLRP3, the upstream proteins of pyroptosis signaling pathway. Besides, the activations of TLR4 and NLRP3 were linearly correlated with the concentrations of pipecolic acid and norepinephrine in the serum of mice. In silenced expression of TLR4 and NLRP3 in HepG2 cells, pipecolic acid or norepinephrine did not able to activate hepatocyte pyroptosis. These results demonstrated the necessity of gut microbial metabolism in sustaining liver homeostasis, as well as the potential to provide new insights into targeted intervention for AFB1 hepatotoxicity.

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The culture of embryos in the non-essential amino acid L-proline (Pro) or its analogues pipecolic acid (PA) and L-4-thiazolidine carboxylic acid (L4T) improves embryo development, increasing the percentage that develop to the blastocyst stage and hatch. Staining of 2-cell and 4-cell embryos with tetramethylrhodamine methyl ester and 2',7'-dichlorofluorescein diacetate showed that the culture of embryos in the presence of Pro, or either of these analogues, reduced mitochondrial activity and reactive oxygen species (ROS), respectively, indicating potential mechanisms by which embryo development is improved. Inhibition of the Pro metabolism enzyme, proline oxidase, by tetrahydro-2-furoic-acid prevented these reductions and concomitantly prevented the improved development. The ways in which Pro, PA and L4T reduce mitochondrial activity and ROS appear to differ, despite their structural similarity. Specifically, the results are consistent with Pro reducing ROS by reducing mitochondrial activity while PA and L4T may be acting as ROS scavengers. All three may work to reduce ROS by contributing to the GSH pool. Overall, our results indicate that reduction in mitochondrial activity and oxidative stress are potential mechanisms by which Pro and its analogues act to improve pre-implantation embryo development.

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Diabetic retinopathy (DR) is currently recognized as the leading cause of end-stage eye disease. Pipecolic acid, a metabolite, has a significant regulatory effect on several pathological processes. However, the exact mechanism by which it causes damage in diabetic retinopathy is unknown. Between September 2021 and December 2022, 40 patients were retrospectively examined and divided into two groups: the healthy group (n = 20) and the DR group (n = 20). Metabolomic analysis found that pipecolic acid plays an important role in this process. Streptozotocin-induced diabetic mice and high-glucose cultured human retinal capillary endothelial cells (HRCECs) were then treated with pipecolic acid. Several oxidative stress measurements and RNA sequencing of retinal cells were tested. A gene interaction study was conducted using bioinformatics. Comparison of serological metabolites between healthy volunteers and DR patients showed that pipecolic acid was significantly lower in DR patients, and there was a negative correlation between the level of pipecolic acid with blood glucose and glycated hemoglobin. Yes-associated protein (YAP) mRNA, Malondialdehyde (MDA), and reactive oxygen species (ROS) levels were significantly higher in diabetic mice, but glutathione peroxidase (GSH-Px) levels were significantly lower. Pipecolic acid significantly alleviated oxidative stress and YAP expression. The number of vascular tubes was significantly higher in the DR group, and pipecolic acid treatment significantly reduced tube formation. RNA-Sequencing analysis revealed that YAP and glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) expression was reduced, and functional enrichment analysis revealed that ferroptosis and Hippo signaling pathways play an important role in this process. Additionally, pipecolic acid's ability to improve DR is diminished after YAP and GPX4 ablation. This study found that pipecolic acid, as a metabolite, may impede the progression of DR by inhibiting the YAP-GPX4 signaling pathway.

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Pipecolic acid (Pip) and N-hydroxypipecolic acid (NHP) have been found to accumulate during the ripening of multiple types of fruits; however, the function and mechanism of pipecolate pathway in fruits remain unclear. Here study was conducted on fruits produced by the model plant tomato, wherein the NHP biosynthesis-related genes, Slald1 and Slfmo1, were mutated. The results showed that the fruits of both the Slald1 and the Slfmo1 mutants exhibited a delayed onset of ripening, decreased fruit size, nutrition and flavor. Exogenous treatment with Pip and NHP promoted fruit ripening and improved fruit quality. Transcriptomic analysis combined with weighted gene co-expression network analysis revealed that the genes involved in the biosynthesis of amino acids, carbon metabolism, photosynthesis, starch and sucrose metabolism, flavonoid biosynthesis, and plant hormone signal transduction were affected by SlFMO1 gene mutation. Transcription factor prediction analysis revealed that the NAC and AP2/ERF-ERF family members are notably involved in the regulation pathway. Overall, our results suggest that the pipecolate biosynthesis pathway is involved in the simultaneous regulation of fruit ripening and quality and indicate that a regulatory mechanism at the transcriptional level exists. However, possible roles of endogenously synthesized Pip and NHP in these processes remain to be determined. The biosynthesis pathway genes SlALD1 and SlFMO1 may be potential breeding targets for promoting fruit ripening and improving fruit quality with concomitant yield increases.

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Tacrolimus (FK506) is an immunosuppressant that is experiencing a continuous rise in usage worldwide. The related side effects are known to be globally dose-dependent. Despite numerous studies on FK506, the mechanisms underlying FK506 toxicity are still not well understood. It is therefore essential to explore the toxicity mediated by FK506. To accomplish this, we conducted a targeted metabolomic analysis using LC-MS on the plasma samples of patients undergoing FK506 treatment. The aim was to identify any associated altered metabolic pathway. Another anti-calcineurin immunosuppressive therapy, ciclosporin (CSA), was also studied. Increased plasma concentrations of pipecolic acid (PA) and sarcosine, along with a decrease in the glycine/sarcosine ratio and a tendency of increased plasma lysine was observed in patients under FK506 compared to control samples. Patients under CSA do not show an increase in plasma PA compared to the control samples, which does not support a metabolic link between the calcineurin and PA. The metabolomics changes observed in patients under FK506 highlight a possible link between FK506 and the action of an enzyme involved in both PA and sarcosine catabolism and oxidative pathway, the Peroxisomal sarcosine oxidase (PIPOX). Moreover, PA could be investigated as a potential biomarker of early nephrotoxicity in the follow-up of patients under FK506.

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In the present study, new methylating agents for the formation of N,N-dimethylpiperidinium (mepiquat) were evaluated in both model and mushroom systems. Mepiquat levels were monitored using five model systems; alanine (Ala)/pipecolic acid (PipAc), methionine (Met)/PipAc, valine (Val)/PipAc, leucine (Leu)/PipAc, and isoleucine (Ile)/PipAc. The highest level of mepiquat was 1.97% at 260 °C for 60 min (Met/PipAc model system). Piperidine can actively combine with methyl groups in thermal reactions to form N-methylpiperidine and mepiquat. Additionally, mushrooms rich in amino acids were oven baked, pan cooked, and deep fried, respectively, to investigate the formation of mepiquat. Oven baking led to the highest mepiquat content of 63.22 ± 0.88 µg/kg. In summary, food constituents are the main source of precursors for mepiquat formation, the mechanism of which has been presented in both model systems and mushroom matrices rich in amino acids.

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Blumeria graminis f. sp. tritici (Bgt) is an obligate biotrophic fungal pathogen responsible for powdery mildew in bread wheat (Triticum aestivum). Upon Bgt infection, the wheat plant activates basal defense mechanisms, namely PAMP-triggered immunity, in the leaves during the first few days. Understanding this early stage of quantitative resistance is crucial for developing new breeding tools and evaluating plant resistance inducers for sustainable agricultural practices. In this sense, we used a combination of transcriptomic and metabolomic approaches to analyze the early steps of the interaction between Bgt and the moderately susceptible wheat cultivar Pakito. Bgt infection resulted in an increasing expression of genes encoding pathogenesis-related (PR) proteins (PR1, PR4, PR5, and PR8) known to target the pathogen, during the first 48 h postinoculation. Moreover, RT-qPCR and metabolomic analyses pointed out the importance of the phenylpropanoid pathway in quantitative resistance against Bgt. Among metabolites linked to this pathway, hydroxycinnamic acid amides containing agmatine and putrescine as amine components accumulated from the second to the fourth day after inoculation. This suggests their involvement in quantitative resistance via cross-linking processes in cell walls for reinforcement, which is supported by the up-regulation of PAL (phenylalanine ammonia-lyase), PR15 (oxalate oxidase) and POX (peroxidase) after inoculation. Finally, pipecolic acid, which is considered a signal involved in systemic acquired resistance, accumulated after inoculation. These new insights lead to a better understanding of basal defense in wheat leaves after Bgt infection.

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In plants, the establishment of broad and long-lasting immunity is based on programs that control systemic resistance and immunological memory or "priming". Despite not showing activated defenses, a primed plant induces a more efficient response to recurrent infections. Priming might involve chromatin modifications that allow a faster/stronger activation of defense genes. The Arabidopsis chromatin regulator "Morpheus Molecule 1" (MOM1) has been recently suggested as a priming factor affecting the expression of immune receptor genes. Here, we show that mom1 mutants exacerbate the root growth inhibition response triggered by the key defense priming inducers azelaic acid (AZA), ß-aminobutyric acid (BABA) and pipecolic acid (PIP). Conversely, mom1 mutants complemented with a minimal version of MOM1 (miniMOM1 plants) are insensitive. Moreover, miniMOM1 is unable to induce systemic resistance against Pseudomonas sp. in response to these inducers. Importantly, AZA, BABA and PIP treatments reduce the MOM1 expression, but not miniMOM1 transcript levels, in systemic tissues. Consistently, several MOM1-regulated immune receptor genes are upregulated during the activation of systemic resistance in WT plants, while this effect is not observed in miniMOM1. Taken together, our results position MOM1 as a chromatin factor that negatively regulates the defense priming induced by AZA, BABA and PIP.

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BACKGROUND: Functional constipation (FC) in children affects their growth, development and quality of life. L-pipecolic acid (L-PA) was decreased in FC children based on gut microbiome and serum metabolomic. In this study, loperamide-induced constipation in mice was used to evaluate the effects of L-PA on constipated mice. METHOD: 26 FC and 28 healthy children were recruited. Stool samples and serum samples were subjected to 16S rDNA sequencing and ultra-performance liquid chromatography/quadrupole time of flight (UPLC-Q/TOF-MS) approach, respectively. A loperamide-induced mouse constipation model was developed, and all mice were randomly divided into control (Con), loperamide (Lop) and L-PA (Lop + L-PA) treatment groups (6 mice per group). The mice in the Lop + L-PA group were given L-PA (250 mg/kg, once a day) and loperamide; the Lop group was given loperamide for 1 week, and the Con group was given saline. The fecal parameters and intestinal motility of mice in each group were detected. serum 5-HT levels and colon 5-HT expression were detected by ELISA and immunohistochemistry, respectively; qRT-PCR was used to detect the expression of AQP3 and 5-HT4R mRNA in each group. RESULTS: 45 differential metabolites and 18 significantly different microbiota were found in FC children. The α and ß diversity of gut microbiota in FC children was significantly reduced. Importantly, serum L-PA was significantly reduced in FC children. The KEGG pathway enrichment were mainly enriched in fatty acid biosynthesis, lysine degradation, and choline metabolism. L-PA was negatively associated with Ochrobactrum, and N6, N6, N6-trimethyl-l-lysine was positively associated with Phascolarcrobacterium. In addition, L-PA improved the fecal water content, intestinal transit rate, and increased the serum 5-HT levels in constipated mice. Moreover, L-PA increased the expression of 5-HT4R, reduced AQP3, and regulated constipation-associated genes. CONCLUSIONS: Gut microbiota and serum metabolites were significantly altered in children with FC. The abundance of Phascolarctobacterium and Ochrobactrum and serum L-PA content were decreased in FC children. L-PA was found to alleviate the fecal water content, increase intestinal transit rate and the first black stool defecation time. L-PA improved constipation by increasing 5-HT and 5-HT4R expression while down-regulating AQP3 expression.

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Plants developed sophisticated mechanisms to perceive environmental stimuli and generate appropriate signals to maintain optimal growth and stress responses. A fascinating strategy employed by plants is the use of long-distance mobile signals which can trigger local and distant responses across the entire plant. Some metabolites play a central role as long-distance mobile signals allowing plants to communicate across tissues and mount robust stress responses. In this review, we summarize the current knowledge regarding the various long-distance mobile metabolites and their functions in stress response and signaling pathways. We also raise questions with respect to how we can identify new mobile metabolites and engineer them to improve plant health and resilience.

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FK-506 is a potent immunosuppressive macrocyclic polyketide with growing pharmaceutical interest, produced by Streptomyces tsukubaensis. However, due to low levels synthesized by the wild-type strain, biotechnological production of FK-506 is rather limited. Optimization strategies to enhance the productivity of S. tsukubaensis by means of genetic engineering have been established. In this work primarily global regulatory aspects with respect to the FK-506 biosynthesis have been investigated with the focus on the global Crp (cAMP receptor protein) regulator. In expression analyses and protein-DNA interaction studies, the role of Crp during FK-506 biosynthesis was elucidated. Overexpression of Crp resulted in two-fold enhancement of FK-506 production in S. tsukubaensis under laboratory conditions. Further optimizations using fermentors proved that the strategy described in this study can be transferred to industrial scale, presenting a new approach for biotechnological FK-506 production. KEY POINTS: • The role of the global Crp (cAMP receptor protein) regulator for FK-506 biosynthesis in S. tsukubaensis was demonstrated • Crp overexpression in S. tsukubaensis was applied as an optimization strategy to enhance FK-506 and FK-520 production resulting in two-fold yield increase.

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Defense responses in plants are based on complex biochemical processes. Systemic acquired resistance (SAR) helps to fight infections by (hemi-)biotrophic pathogens. One important signaling molecule in SAR is pipecolic acid (Pip), accumulation of which is dependent on the aminotransferase ALD1 in Arabidopsis. While exogenous Pip primes defense responses in the monocotyledonous cereal crop barley (Hordeum vulgare), it is currently unclear if endogenous Pip plays a role in disease resistance in monocots. Here, we generated barley ald1 mutants using CRISPR/Cas9, and assessed their capacity to mount SAR. Endogenous Pip levels were reduced after infection of the ald1 mutant, and this altered systemic defense against the fungus Blumeria graminis f. sp. hordei. Furthermore, Hvald1 plants did not emit nonanal, one of the key volatile compounds that are normally emitted by barley plants after the activation of SAR. This resulted in the inability of neighboring plants to perceive and/or respond to airborne cues and prepare for an upcoming infection, although HvALD1 was not required in the receiver plants to mediate the response. Our results highlight the crucial role of endogenous HvALD1 and Pip for SAR, and associate Pip, in particular together with nonanal, with plant-to-plant defense propagation in the monocot crop barley.

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The nonproteinogenic cyclic metabolite l-pipecolic acid is a chiral precursor for the synthesis of various commercial drugs and functions as a cell-protective extremolyte and mediator of defense in plants, enabling high-value applications in the pharmaceutical, medical, cosmetic, and agrochemical markets. To date, the production of the compound is unfavorably fossil-based. Here, we upgraded the strain Corynebacterium glutamicum for l-pipecolic acid production using systems metabolic engineering. Heterologous expression of the l-lysine 6-dehydrogenase pathway, apparently the best route to be used in the microbe, yielded a family of strains that enabled successful de novo synthesis from glucose but approached a limit of performance at a yield of 180 mmol mol-1. Detailed analysis of the producers at the transcriptome, proteome, and metabolome levels revealed that the requirements of the introduced route were largely incompatible with the cellular environment, which could not be overcome after several further rounds of metabolic engineering. Based on the gained knowledge, we based the strain design on l-lysine 6-aminotransferase instead, which enabled a substantially higher in vivo flux toward l-pipecolic acid. The tailormade producer C. glutamicum PIA-7 formed l-pipecolic acid up to a yield of 562 mmol mol-1, representing 75% of the theoretical maximum. Ultimately, the advanced mutant PIA-10B achieved a titer of 93 g L-1 in a fed-batch process on glucose, outperforming all previous efforts to synthesize this valuable molecule de novo and even approaching the level of biotransformation from l-lysine. Notably, the use of C. glutamicum allows the safe production of GRAS-designated l-pipecolic acid, providing extra benefit toward addressing the high-value pharmaceutical, medical, and cosmetic markets. In summary, our development sets a milestone toward the commercialization of biobased l-pipecolic acid.

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In plants, salicylic acid (SA) is a central immune signal that is involved in both local and systemic acquired resistance (SAR). In addition to SA, several other chemical signals are also involved in SAR and these include N-hydroxy-pipecolic acid (NHP), a newly discovered plant metabolite that plays a crucial role in SAR. Recent discoveries have led to a better understanding of the biosynthesis of SA and NHP and their signaling during plant defense responses. Here, I review the recent progress in role of SA and NHP in SAR. In addition, I discuss how these signals cooperate with other SAR-inducing chemicals to regulate SAR.

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Plants prevent disease by passively and actively protecting potential entry routes against invading microbes. For example, the plant immune system actively guards roots, wounds, and stomata. How plants prevent vascular disease upon bacterial entry via guttation fluids excreted from specialized glands at the leaf margin remains largely unknown. These so-called hydathodes release xylem sap when root pressure is too high. By studying hydathode colonization by both hydathode-adapted (Xanthomonas campestris pv. campestris) and non-adapted pathogenic bacteria (Pseudomonas syringae pv. tomato) in immunocompromised Arabidopsis mutants, we show that the immune hubs BAK1 and EDS1-PAD4-ADR1 restrict bacterial multiplication in hydathodes. Both immune hubs effectively confine bacterial pathogens to hydathodes and lower the number of successful escape events of an hydathode-adapted pathogen toward the xylem. A second layer of defense, which is dependent on the plant hormones' pipecolic acid and to a lesser extent on salicylic acid, reduces the vascular spread of the pathogen. Thus, besides glands, hydathodes represent a potent first line of defense against leaf-invading microbes.

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Pipecolic acid (Pip) and its derivative hydroxypipecolic acids, such as (2S,3R)-3-hydroxypipecolic acid (cis-3-L-HyPip), are components of many natural and synthetic bioactive molecules. Fe(II)/α-ketoglutaric acid (Fe(II)/2-OG)-dependent dioxygenases can catalyze the hydroxylation of pipecolic acid. However, the available enzymes with desired activity and selectivity are limited. Herein, we compare the possible candidates in the Fe(II)/2-OG-dependent dioxygenase family, and cis-P3H is selected for potentially catalyzing selective hydroxylation of L-Pip. cis-P3H was further engineered to increase its catalytic efficiency toward L-Pip. By analyzing the structural confirmation and residue composition in substrate-binding pocket, a "handlebar" mode of molecular interactions is proposed. Using molecular docking, virtual mutation analysis, and dynamic simulations, R97, E112, L57, and G282 were identified as the key residues for subsequent site-directed saturation mutagenesis of cis-P3H. Consequently, the variant R97M showed an increased catalytic efficiency toward L-Pip. In this study, the kcat/Km value of the positive mutant R97M was about 1.83-fold that of the wild type. The mutation R97M would break the salt bridge between R97 and L-Pip and weaken the positive-positive interaction between R97 and R95. Therefore, the force on the amino and carboxyl groups of L-Pip was lightly balanced, allowing the molecule to be stabilized in the active pocket. These results provide a potential way of improving cis-P3H catalytic activity through rational protein engineering.

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Bacteria, filamentous fungi, and plants synthesize thousands of secondary metabolites with important biological and pharmacological activities. The biosynthesis of these metabolites is performed by networks of complex enzymes such as non-ribosomal peptide synthetases, polyketide synthases, and terpenoid biosynthetic enzymes. The efficient production of these metabolites is dependent upon the supply of precursors that arise from primary metabolism. In the last decades, an impressive array of biosynthetic enzymes that provide specific precursors and intermediates leading to secondary metabolites biosynthesis has been reported. Suitable knowledge of the elaborated pathways that synthesize these precursors or intermediates is essential for advancing chemical biology and the production of natural or semisynthetic biological products. Two of the more prolific routes that provide key precursors in the biosynthesis of antitumor, immunosuppressant, antifungal, or antibacterial compounds are the lysine and ornithine pathways, which are involved in the biosynthesis of ß-lactams and other non-ribosomal peptides, and bacterial and fungal siderophores. Detailed analysis of the molecular genetics and biochemistry of the enzyme system shows that they are formed by closely related components. Particularly the focus of this study is on molecular genetics and the enzymatic steps that lead to the formation of intermediates of the lysine pathway, such as α-aminoadipic acid, saccharopine, pipecolic acid, and related compounds, and of ornithine-derived molecules, such as N5-Acetyl-N5-Hydroxyornithine and N5-anhydromevalonyl-N5-hydroxyornithine, which are precursors of siderophores. We provide evidence that shows interesting functional relationships between the genes encoding the enzymes that synthesize these products. This information will contribute to a better understanding of the possibilities of advancing the industrial applications of synthetic biology.