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Sjögren–Larsson syndrome (SLS) is a rare inherited neurocutaneous disease characterized by ichthyosis, spastic diplegia or tetraplegia, intellectual disability and a distinctive retinopathy. SLS is caused by bi-allelic mutations in ALDH3A2, which codes for fatty aldehyde dehydrogenase (FALDH) and results in abnormal lipid metabolism. The biochemical abnormalities in SLS are not completely known, and the pathogenic mechanisms leading to symptoms are still unclear. To search for pathways that are perturbed in SLS, we performed untargeted metabolomic screening in 20 SLS subjects along with age- and sex-matched controls. Of 823 identified metabolites in plasma, 121 (14.7%) quantitatively differed in the overall SLS cohort from controls; 77 metabolites were decreased and 44 increased. Pathway analysis pointed to disrupted metabolism of sphingolipids, sterols, bile acids, glycogen, purines and certain amino acids such as tryptophan, aspartate and phenylalanine. Random forest analysis identified a unique metabolomic profile that had a predictive accuracy of 100% for discriminating SLS from controls. These results provide new insight into the abnormal biochemical pathways that likely contribute to disease in SLS and may constitute a biomarker panel for diagnosis and future therapeutic studies. [ABSTRACT FROM AUTHOR]

The oxidation of a series of fatty alcohols to yield the corresponding aldehydes is performed using RuCl3 ⋅ (H2O)x as a homogeneous catalyst and inexpensive trimethylamine N‐oxide (TMAO) as the oxygen source. The reaction conditions were optimized for both high conversion and high selectivity. [ABSTRACT FROM AUTHOR]

Weed species many times possess allelochemicals as a part of their survival strategy. These metabolites can be potential targets in search of natural phytotoxins. This study aims to evaluate the phytotoxic ability of fatty aldehyde-rich essential oil from spiny coriander (Eryngium foetidum) leaves, also known as fitweed or spiritweed and to further identify the active phytotoxins. This oil dose-dependently inhibited the wheatgrass coleoptile and radicle growth in multiple bioassays with half maximal inhibitory concentration (IC 50 ) 30.6-56.7 μg/mL, while exhibiting a less pronounced effect on the germination (IC 50 181.8 μg/mL). The phytotoxicity assessment of two oil constituents identified eryngial (trans-2-dodecenal), exclusively major fatty aldehydic constituent as the potent growth inhibitor with IC 50 in the range 20.8-36.2 μg/mL during an early phase of wheatgrass emergence. Eryngial-inspired screening of eleven saturated fatty aldehydes and alcohols did not find a significantly higher phytotoxic potency. In an open vessel, eryngial as the supplementation in agar medium, dose-dependently inhibited the growth of pre-germinated seeds of one monocot (bermudagrass) and one dicot (green amaranth) weed species with IC 50 in the range 23.8-65.4 μg/mL. The current study identified eryngial, an α,β-unsaturated fatty aldehyde of coriander origin to be a promising phytotoxic candidate for weed control., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Sjögren–Larsson syndrome (SLS) is a rare inherited neurocutaneous disease characterized by ichthyosis, spastic diplegia or tetraplegia, intellectual disability and a distinctive retinopathy. SLS is caused by bi-allelic mutations in ALDH3A2, which codes for fatty aldehyde dehydrogenase (FALDH) and results in abnormal lipid metabolism. The biochemical abnormalities in SLS are not completely known, and the pathogenic mechanisms leading to symptoms are still unclear. To search for pathways that are perturbed in SLS, we performed untargeted metabolomic screening in 20 SLS subjects along with age- and sex-matched controls. Of 823 identified metabolites in plasma, 121 (14.7%) quantitatively differed in the overall SLS cohort from controls; 77 metabolites were decreased and 44 increased. Pathway analysis pointed to disrupted metabolism of sphingolipids, sterols, bile acids, glycogen, purines and certain amino acids such as tryptophan, aspartate and phenylalanine. Random forest analysis identified a unique metabolomic profile that had a predictive accuracy of 100% for discriminating SLS from controls. These results provide new insight into the abnormal biochemical pathways that likely contribute to disease in SLS and may constitute a biomarker panel for diagnosis and future therapeutic studies.

Sjögren-Larsson syndrome (SLS) is a neurocutaneous disease caused by mutations in ALDH3A2 that result in deficient fatty aldehyde dehydrogenase (FALDH) activity and impaired fatty aldehyde and fatty alcohol oxidation. The pathogenesis of SLS is thought to involve accumulation of long-chain fatty aldehydes and alcohols and/or metabolically-related ether glycerolipids. Fatty aldehydes are particularly toxic molecules that can covalently react with proteins and certain amino-containing lipids such as phosphatidylethanolamine (PE), generating an unusual aldehyde adduct, N-alkyl-PE (NAPE). Using Faldh-deficient Chinese hamster ovary cells (FAA-K1A) as a cellular model for SLS, we investigated the ability of an aldehyde trapping agent, ADX-102 [2-(3-amino-6-chloro-quinolin-2-yl)-propan-2-ol], to mitigate the harmful effects of fatty aldehydes. FAA-K1A cells were protected from octadecanal (C18:0-al) induced cytotoxicity and apoptosis by ADX-102. Metabolism of C18:0-al to fatty alcohol (octadecanol) was also inhibited by ADX-102. FAA-K1A cells accumulated 5-fold more NAPE with C16- and C18-linked N-alkyl chains compared to wild-type cells, but NAPE levels decreased to normal after growth for 4 days with 50 μM ADX-102. Our results suggest that small aldehyde-reactive molecules, such as ADX-102, should be explored as novel therapeutic agents for SLS by preventing aldehyde adduct formation with critical cellular targets and inhibiting fatty aldehyde metabolism to fatty alcohol.

α-Dioxygenases (α-DOXs) are known as plant enzymes involved in the α-oxidation of fatty acids through which fatty aldehydes, with a high commercial value as flavor and fragrance compounds, are synthesized as products. Currently, little is known about α-DOXs from non-plant organisms. The phylogenic analysis reported here identified a substantial number of α-DOX enzymes across various taxa. Here, we report the functional characterization and Escherichia coli whole-cell application of two novel α-DOXs identified from cyanobacteria: CalDOX from Calothrix parietina and LepDOX from Leptolyngbya sp. The catalytic behavior of the recombinantly expressed CalDOX and LepDOX revealed that they are heme-dependent like plant α-DOXs but exhibit activities toward medium carbon fatty acids ranging from C10 to C14 unlike plant α-DOXs. The in-depth molecular investigation of cyanobacterial α-DOXs and their application in an E. coli whole system employed in this study is useful not only for the understanding of the molecular function of α-DOXs, but also for their industrial utilization in fatty aldehyde biosynthesis. Key points • Two novel α-dioxygenases from Cyanobacteria are reported • Both enzymes prefer medium-chain fatty acids • Both enzymes are useful for fatty aldehyde biosynthesis [ABSTRACT FROM AUTHOR]

Sjögren-Larsson syndrome is a genetic disease characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene coding for fatty aldehyde dehydrogenase, an enzyme necessary for oxidation of fatty aldehydes and fatty alcohols. We investigated the cutaneous abnormalities in 9 patients with Sjögren-Larsson syndrome to better understand how the enzymatic deficiency results in epidermal dysfunction. Histochemical staining for aldehyde oxidizing activity was profoundly reduced in the epidermis. Colloidal lanthanum perfusion studies showed abnormal movement of tracer into the extracellular spaces of the stratum corneum consistent with a leaky water barrier. The barrier defect could be attributed to the presence of abnormal lamellar bodies, many with disrupted limiting membranes or lacking lamellar contents. Entombed lamellar bodies were present in the cytoplasm of corneocytes suggesting blockade of lamellar body secretion. At the stratum granulosum-stratum corneum interface, non-lamellar material displaced or replaced secreted lamellar membranes, and in the stratum corneum, the number of lamellar bilayers declined and lamellar membrane organization was disrupted by foci of lamellar/non-lamellar phase separation. These studies demonstrate the presence of a permeability barrier abnormality in Sjögren-Larsson syndrome, which localizes to the stratum corneum interstices and can be attributed to abnormalities in lamellar body formation and secretion.

Abstract Background Fatty aldehydes are industrially relevant compounds, which also represent a common metabolic intermediate in the microbial synthesis of various oleochemicals, including alkanes, fatty alcohols and wax esters. The key enzymes in biological fatty aldehyde production are the fatty acyl-CoA/ACP reductases (FARs) which reduce the activated acyl molecules to fatty aldehydes. Due to the disparity of FARs, identification and in vivo characterization of reductases with different properties are needed for the construction of tailored synthetic pathways for the production of various compounds. Results Fatty aldehyde production in Acinetobacter baylyi ADP1 was increased by the overexpression of three different FARs: a native A. baylyi FAR Acr1, a cyanobacterial Aar, and a putative, previously uncharacterized dehydrogenase (Ramo) from Nevskia ramosa. The fatty aldehyde production was followed in real-time inside the cells with a luminescence-based tool, and the highest aldehyde production was achieved with Aar. The fate of the overproduced fatty aldehydes was studied by measuring the production of wax esters by a native downstream pathway of A. baylyi, for which fatty aldehyde is a specific intermediate. The wax ester production was improved with the overexpression of Acr1 or Ramo compared to the wild type A. baylyi by more than two-fold, whereas the expression of Aar led to only subtle wax ester production. The overexpression of FARs did not affect the length of the acyl chains of the wax esters. Conclusions The fatty aldehyde production, as well as the wax ester production of A. baylyi, was improved with the overexpression of a key enzyme in the pathway. The wax ester titer (0.45 g/l) achieved with the overexpression of Acr1 is the highest reported without hydrocarbon supplementation to the culture. The contrasting behavior of the different reductases highlight the significance of in vivo characterization of enzymes and emphasizes the possibilities provided by the diversity of FARs for pathway and product modulation.

Sjögren-Larsson syndrome (SLS) is a rare genetic neurocutaneous disease caused by mutations in ALDH3A2 that results in deficiency of fatty aldehyde dehydrogenase and accumulation of fatty aldehydes and alcohols. The disease is associated with ichthyosis, spasticity, and intellectual disability. Patients exhibit a characteristic retinopathy with macular crystalline inclusions that first appear in early childhood and increase with age. Once formed, the inclusions are thought to be inert and irreversible. We sought to document how the crystalline inclusions change over time. Serial retinal photographs of 4 SLS subjects (9–23 years old) were taken over a period of 1–3 years. Images were compared by visual inspection and analyzed using ImageJ/Fiji software to observe changes. Visual inspection of retinal photographs of SLS subjects taken over time demonstrated distinctive changes in crystalline inclusions. New inclusions were formed and some established inclusions regressed. These changes were conveniently demonstrated with software-based photographic image analysis. We conclude that macular inclusions in SLS are not simply inert deposits, but are dynamic structures that form over time and are subject to remodeling. This conclusion provides new insight into the interplay between the metabolic defect and retinal pathology in SLS, and raises the potential for new therapeutic approaches to reverse some aspects of the maculopathy. [ABSTRACT FROM AUTHOR]

• Aldehyde/alcohol ratios differ largely in αDox- or CAR-catalyzed biotransformations. • Catabolic redox state of CAR-expressing probably the reason for the high aldehyde reduction activity. • Undecanal product titer 10 mM using αDox, dodecanol product titer 6 mM using Car. • E. coli fatty aldehyde dehydrogenase activity produces C 12 , C 11 , C 10 and C 9 fatty acids. Fatty aldehydes are among the most important flavor and fragrance compounds. Most biotechnological production approaches make use of the one step conversion of fatty acids from renewable sources by the enzymes α-dioxygenase (αDox) or carboxylic acid reductase (CAR). Their reaction mechanisms and cofactor dependencies are very different. In contrast to heme-containing αDox which requires only oxygen as cosubstrate, CAR needs NADPH and ATP, which is a clear argument for the application of a whole cell catalyst. Therefore we compared fatty acid biotransformations with growing Escherichia coli cells expressing αDox or CAR to investigate their suitability for fatty aldehyde and also fatty alcohol production. Our results show the main product of fatty acid conversions with αDox-expressing cells to be the expected C n-1 aldehyde. However, 14% of the products consist of the corresponding alcohol, but in addition, 17% of the products consist of further shortened aldehydes, alcohols and acids that result from the consecutive activity of αDox and a putative endogenous fatty aldehyde dehydrogenase activity in E. coli. Conversely, CAR-expressing cells produced only the unshortened fatty aldehyde and alcohol, whereby the latter surprisingly accounts for at least 80% of the products. The considerably higher extend of aldehyde reduction of CAR-expressing cells was shown to be causally connected to the CAR-mediated fatty acid conversion. Our study provides an overview about the applicability of αDox- or CAR-based whole cell catalysts and gives a detailed description of side products as well as suggestions for tailored strain engineering. [ABSTRACT FROM AUTHOR]

Purpose: Sjögren-Larsson Syndrome (SLS) is a rare genetic disorder characterized by a distinctive crystalline maculopathy, congenital ichthyosis, spasticity and intellectual disability. We review the genetic, biochemical and clinical aspects of SLS with a particular focus on the ophthalmologic features of the disease.Methods: Published reports of SLS are combined with clinical experience to provide an overview of this disease.Results: SLS is caused by bi-allelic mutations in ALDH3A2, which codes for fatty aldehyde dehydrogenase, a key enzyme needed for the metabolism of long-chain aliphatic aldehydes and alcohols. SLS patients display perifoveal crystalline inclusions (glistening white dots) that appear in early childhood, vary from sparse to florid and are located in the inner retina. Other findings include retinal thinning, cystic macular degeneration, retinal pigment epithelium atrophy and deficiency of macular pigment. Photophobia is common. Visual evoked potentials are often absent or delayed, whereas electroretinography studies are usually normal. Mild-moderate deficits in visual acuity are common but vision is usually preserved into adulthood. The maculopathy is thought to be due to the accumulation of fatty aldehydes and/or alcohols, which alter membrane function. Defective macular pigment metabolism may also contribute to a unique susceptibility to photo-oxidative damage in the retina.Conclusions: The distinctive retinal phenotype, together with the neurologic and cutaneous symptoms, allows the ophthalmologist to reliably diagnose SLS. Although no effective treatment exists for the ocular symptoms, emerging insight into the pathogenic mechanisms at play in the eye promises to bring effective therapy for SLS in the future. [ABSTRACT FROM AUTHOR]

Background: Biosynthesis of alkanes is an attractive way of producing substitutes for petroleum-based alkanes. Acyl- [acyl carrier protein (ACP)] reductase (AAR) is a key enzyme for alkane biosynthesis in cyanobacteria and catalyzes the reduction of fatty acyl-ACP to fatty aldehydes, which are then converted into alkanes/alkenes by aldehyde-deformylating oxygenase (ADO). The amino acid sequences of AARs vary among cyanobacteria. However, their differences in catalytic activity, substrate specificity, and solubility are poorly understood. Results: We compared the aldehyde-producing activity, substrate specificity, and solubility of AARs from 12 representative cyanobacteria. The activity is the highest for AAR from Synechococcus elongatus PCC 7942, followed by AAR from Prochlorococcus marinus MIT 9313. On the other hand, protein solubility is high for AARs from PCC 7942, Microcystis aeruginosa, Thermosynechococcus elongatus BP-1, Synechococcus sp. RS9917, and Synechococcus sp. CB0205. As a consequence, the amount of alkanes/alkenes produced in Escherichia coli coexpressing AAR and ADO is the highest for AAR from PCC 7942, followed by AARs from BP-1 and MIT 9313. Strikingly, AARs from marine and freshwater cyanobacteria tend to have higher specificity toward the substrates with 16 and 18 carbons in the fatty acyl chain, respectively, suggesting that the substrate specificity of AARs correlates with the type of habitat of host cyanobacteria. Furthermore, mutational analysis identified several residues responsible for the high activity of AAR. Conclusions: We found that the activity, substrate specificity, and solubility are diverse among various AARs. Our results provide a basis for selecting an AAR sequence suitable for metabolic engineering of bioalkane production while regulating carbon chain length. [ABSTRACT FROM AUTHOR]

Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder characterized by ichthyosis, mental retardation, spasticity, and deficient activity of fatty aldehyde dehydrogenase (FALDH). FALDH is an enzyme component of fatty alcohol:NAD oxidoreductase (FAO), which is necessary for fatty alcohol metabolism. To better understand the biochemical basis for the cutaneous symptoms in this disease, we investigated lipid metabolism in cultured keratinocytes from SLS patients. Enzyme activities of FALDH and FAO in SLS cells were

Long chain fatty alcohols have wide application in chemical industries and transportation sector. There is no direct natural reservoir for long chain fatty alcohol production, thus many groups explored metabolic engineering approaches for its microbial production. Escherichia coli has been the major microbial platform for this effort, however, terminal endogenous enzyme responsible for converting fatty aldehydes of chain length C14-C18 to corresponding fatty alcohols is still been elusive. Through our in silico analysis we selected 35 endogenous enzymes of E. coli having potential of converting long chain fatty aldehydes to fatty alcohols and studied their role under in vivo condition. We found that deletion of ybbO gene, which encodes NADP + dependent aldehyde reductase, led to >90% reduction in long chain fatty alcohol production. This feature was found to be strain transcending and reinstalling ybbO gene via plasmid retained the ability of mutant to produce long chain fatty alcohols. Enzyme kinetic study revealed that YbbO has wide substrate specificity ranging from C6 to C18 aldehyde, with maximum affinity and efficiency for C18 and C16 chain length aldehyde, respectively. Along with endogenous production of fatty aldehyde via optimized heterologous expression of cyanobaterial acyl-ACP reductase (AAR), YbbO overexpression resulted in 169 mg/L of long chain fatty alcohols. Further engineering involving modulation of fatty acid as well as of phospholipid biosynthesis pathway improved fatty alcohol production by 60%. Finally, the engineered strain produced 1989 mg/L of long chain fatty alcohol in bioreactor under fed-batch cultivation condition. Our study shows for the first time a predominant role of a single enzyme in production of long chain fatty alcohols from fatty aldehydes as well as of modulation of phospholipid pathway in increasing the fatty alcohol production. [ABSTRACT FROM AUTHOR]

Fatty aldehydes (FALs) are involved in various biological processes, and their abnormal metabolism is related to the occurrence and development of neurological diseases. Because of their low ionization efficiency, methods for in situ detection and mass spectrometry imaging (MSI) analysis of FALs remain underreported. On-tissue chemical tagging of hardly ionizable target analytes with easily ionized moieties can improve ionization efficiency and detection sensitivity in MSI experiments. In this study, an on-tissue chemical derivatization-air-flow-assisted desorption electrospray ionization-MSI method was developed to visualize FALs in the rat brain. The method showed high sensitivity and specificity, allowing the use of in situ high-resolution MS 3 to identify FALs. The methodology was applied to investigate the region-specific distribution of FALs in the brains of control and diabetic encephalopathy (DE) rats. In DE rats, FALs were found to be significantly enriched in various brain regions, especially in the cerebral cortex, hippocampus, and amygdala. Thus, increased FAL levels and oxidative stress occurred in a region-dependent manner, which may contribute to cognitive function deficits in DE. In summary, we provide a novel method for the in situ detection of FALs in biological tissues as well as new insights into the potential pathogenesis of DE.

A novel galactosylalkylglycerol modified with a long-chain cyclic acetal at the sugar moiety, 3-O-(4′6′-plasmalogalactosyl) 1-O-alkylglycerol, was isolated from equine brain. The presence of cyclic acetal linkage, its linked position, and the length of the acetal chain of the natural plasmalo lipid were determined by proton NMR spectroscopy and fast-atom bombardment–mass spectrometry, as well as gas chromatography–mass spectrometry and gas–liquid chromatography. To identify the isomeric stereostructure of the natural product, the plasmalo derivative was chemically synthesized from 3-O-galactosyl 2-O-acyl 1-O-alkyl glyceride through acetalization after deacylation. As a result, the direction and position of the acetal chain of the natural plasmalo lipid were characterized as an “endo”-type 4′,6′-O-acetal derivative linked to galactoside by comparison with the NMR data of the synthesized product. The chain lengths of alkyl and acetal groups were C14 for the former and C16 and C18 for the latter, and those for the latter group were mostly similar to those of plasmalogalactosyl ceramide, which was previously isolated from equine brain.—Yachida, Y., M. Kashiwagi, T. Mikami, K. Tsuchihashi, T. Daino, T. Akino, and S. Gasa. Novel plasmalogalactosylalkylglycerol from equine brain.

Modified galactosylceramide with a long-chain cyclic acetal at the sugar moiety, plasmalogalactosylceramide, was isolated from equine brain. To identify the isomeric stereostructure of the natural product, the plasmalo derivative was chemically synthesized from galactosylceramide through acetalization. The presence of cyclic acetal linkage, the linked position and length of the acetal chain of the synthesized and natural products were determined by proton nuclear magnetic resonance spectroscopy and fast-atom bombardment–mass spectrometry, as well as gas chromatography–mass spectrometry and gas–liquid chromatography. The orientation of the acetal chain linked to galactoside was characterized by connectivity between the cyclic acetal proton and ring proton(s) on the sugar moiety using the homonuclear Overhauser effect. This revealed that, of the two positional isomers of the acetal linkage with 4,6-O-acetal and 3,4-O-acetal derivatives obtained from the acetalization reaction, the former positional isomer, separated into two spots, was identified to 'endo'- and 'exo'-type acetal chains. In comparison to the NMR data of the synthesized derivative, equine brain acetalized lipid was found to be an 'endo'-type 4,6-O-acetal derivative.—Yachida, Y., M. Kashiwagi, T. Mikami, K. Tsuchihashi, T. Daino, T. Akino, and S. Gasa. Stereochemical structures of synthesized and natural plasmalogalactosylceramides from equine brain. J. Lipid Res. 1998. 39: 1039–1045.

Abstract: Leukocytes are key cellular mediators of human diseases through their role in inflammation. Identifying unique molecules produced by leukocytes may provide new biomarkers and mechanistic insights into the role of leukocytes in disease. Chlorinated lipids are generated as a result of myeloperoxidase-containing leukocyte-derived hypochlorous acid targeting the vinyl ether bond of plasmalogens. The initial product of this reaction is α-chlorofatty aldehyde. α-Chlorofatty aldehyde is both oxidized to α-chlorofatty acid and reduced to α-chlorofatty alcohol by cellular metabolism. This review focuses on the separation techniques and quantitative analysis for these chlorinated lipids. For α-chlorofatty acid, the negative charge of carboxylic acids is exploited to detect the chlorinated lipid species of these acids by electrospray ionization mass spectrometry in the negative ion mode. In contrast, α-chlorofatty aldehyde and α-chlorofatty alcohol are converted to pentafluorobenzyl oxime and pentafluorobenzoyl ester derivatives, which are detected by negative ion chemical ionization mass spectrometry. These two detection methods coupled with the use of stable isotope internal standards and either liquid chromatography or gas chromatography provide highly sensitive analytical approaches to measure these novel lipids. [Copyright &y& Elsevier]

• Synthesis an isotope-coded derivative for high-effective derivatising aldehydes. • The derivatisation reaction was performed at 20 °C for 15 min with no byproduct. • Remarkably enhance separation performance and detection sensitivity of aldehydes. • Effectively minimizing matrix effects using isotope-coded quantitative method. Fatty aldehydes are the end products of lipid peroxides and are involved in a wide range of cellular biological pathways, food quality and flavour. However, the quantitative methods of analysing fatty aldehydes are limited due to the neutral properties of the carbonyl group, and their hydrophilicity and instability. In this study, a comprehensive isotope-coded derivative, 5-(dimethylamino)-1-carbohydrazide-isoquinoline (DMAQ), was developed for sensitive and accurate quantitative analysis of fatty aldehydes. The derivatives can remarkably improve the ionisation efficiency and separation performance of aldehydes and minimise matrix effects. The limit of detection of derivatised aldehydes was as low as 0.09 ng/L. The intra-day and inter-day relative standard deviations were well below 5.24 % and 7.97 %, respectively. This new method was successfully applied in fatty aldehyde analysis of fresh meat under different post-harvest processes. These results demonstrated that isotope-coded DMAQ derivatisation provides a useful tool for quantifying fatty aldehydes in complex biological samples with high accuracy and precision. [ABSTRACT FROM AUTHOR]