scholarly journals Nuclear receptors NHR-49 and NHR-79 promote peroxisome proliferation to compensate for aldehyde dehydrogenase deficiency in C. elegans

PLoS Genetics ◽  
2021 ◽  
Vol 17 (7) ◽  
pp. e1009635
Author(s):  
Lidan Zeng ◽  
Xuesong Li ◽  
Christopher B. Preusch ◽  
Gary J. He ◽  
Ningyi Xu ◽  
...  
Keyword(s):  
Aldehyde Dehydrogenase ◽  
Therapeutic Strategy ◽  
Fatty Aldehyde ◽  
Peroxisome Proliferation ◽  
Imaging Analysis ◽  
Neurologic Disorder ◽  
Aldehyde Dehydrogenases ◽  
C Elegans ◽  
Catabolic Enzymes ◽  
Fatty Aldehydes

The intracellular level of fatty aldehydes is tightly regulated by aldehyde dehydrogenases to minimize the formation of toxic lipid and protein adducts. Importantly, the dysregulation of aldehyde dehydrogenases has been implicated in neurologic disorder and cancer in humans. However, cellular responses to unresolved, elevated fatty aldehyde levels are poorly understood. Here, we report that ALH-4 is a C. elegans aldehyde dehydrogenase that specifically associates with the endoplasmic reticulum, mitochondria and peroxisomes. Based on lipidomic and imaging analysis, we show that the loss of ALH-4 increases fatty aldehyde levels and reduces fat storage. ALH-4 deficiency in the intestine, cell-nonautonomously induces NHR-49/NHR-79-dependent hypodermal peroxisome proliferation. This is accompanied by the upregulation of catalases and fatty acid catabolic enzymes, as indicated by RNA sequencing. Such a response is required to counteract ALH-4 deficiency since alh-4; nhr-49 double mutant animals are sterile. Our work reveals unexpected inter-tissue communication of fatty aldehyde levels and suggests pharmacological modulation of peroxisome proliferation as a therapeutic strategy to tackle pathology related to excess fatty aldehydes.

scholarly journals Nuclear receptor NHR-49 promotes peroxisome proliferation to compensate for aldehyde dehydrogenase deficiency in C. elegans

2020 ◽  
Author(s):  
Lidan Zeng ◽  
Xuesong Li ◽  
Christopher B. Preusch ◽  
Gary J. He ◽  
Ningyi Xu ◽  
...  
Keyword(s):  
Aldehyde Dehydrogenase ◽  
Therapeutic Strategy ◽  
Fatty Aldehyde ◽  
Peroxisome Proliferation ◽  
Neurologic Disorder ◽  
C Elegans ◽  
Catabolic Enzymes ◽  
Cellular Components ◽  
Fatty Aldehydes ◽  
Larsson Syndrome

AbstractThe intracellular level of fatty aldehydes is tightly regulated to minimize the formation of toxic aldehyde adducts of cellular components. Accordingly, deficiency of a fatty aldehyde dehydrogenase FALDH causes the neurologic disorder Sjögren-Larsson syndrome (SLS) in humans. However, cellular responses to unresolved, elevated fatty aldehyde levels are poorly understood. Based on lipidomic and imaging analysis, we report that the loss of endoplasmic reticulum-, mitochondria- and peroxisomes-associated ALH-4, the C. elegans FALDH ortholog, increases fatty aldehyde levels and reduces fat storage. ALH-4 deficiency in the intestine, cell-nonautonomously induces NHR-49/NHR-79-dependent hypodermal peroxisome proliferation. This is accompanied by the upregulation of catalases and fatty acid catabolic enzymes, as indicated by RNA sequencing. Such a response is required to counteract ALH-4 deficiency since alh-4; nhr-49 double mutant animals are not viable. Our work reveals unexpected inter-tissue communication of fatty aldehyde levels, and suggests pharmacological modulation of peroxisome proliferation as a therapeutic strategy for SLS.

scholarly journals Five Fatty Aldehyde Dehydrogenase Enzymes from Marinobacter and Acinetobacter spp. and Structural Insights into the Aldehyde Binding Pocket

2017 ◽  
Vol 83 (12) ◽  
Author(s):  
Jonathan H. Bertram ◽  
Kalene M. Mulliner ◽  
Ke Shi ◽  
Mary H. Plunkett ◽  
Peter Nixon ◽  
...  
Keyword(s):  
Aldehyde Dehydrogenase ◽  
Binding Pocket ◽  
Fatty Aldehyde ◽  
Acinetobacter Baylyi ◽  
Central Function ◽  
Content Type ◽  
Energy Conversion And Storage ◽  
Acinetobacter Spp ◽  
Fatty Aldehydes ◽  
And Storage

ABSTRACT Enzymes involved in lipid biosynthesis and metabolism play an important role in energy conversion and storage and in the function of structural components such as cell membranes. The fatty aldehyde dehydrogenase (FAldDH) plays a central function in the metabolism of lipid intermediates, oxidizing fatty aldehydes to the corresponding fatty acid and competing with pathways that would further reduce the fatty aldehydes to fatty alcohols or require the fatty aldehydes to produce alkanes. In this report, the genes for four putative FAldDH enzymes from Marinobacter aquaeolei VT8 and an additional enzyme from Acinetobacter baylyi were heterologously expressed in Escherichia coli and shown to display FAldDH activity. Five enzymes (Maqu_0438, Maqu_3316, Maqu_3410, Maqu_3572, and the enzyme reported under RefSeq accession no. WP_004927398 ) were found to act on aldehydes ranging from acetaldehyde to hexadecanal and also acted on the unsaturated long-chain palmitoleyl and oleyl aldehydes. A comparison of the specificities of these enzymes with various aldehydes is presented. Crystallization trials yielded diffraction-quality crystals of one particular FAldDH (Maqu_3316) from M. aquaeolei VT8. Crystals were independently treated with both the NAD+ cofactor and the aldehyde substrate decanal, revealing specific details of the likely substrate binding pocket for this class of enzymes. A likely model for how catalysis by the enzyme is accomplished is also provided. IMPORTANCE This study provides a comparison of multiple enzymes with the ability to oxidize fatty aldehydes to fatty acids and provides a likely picture of how the fatty aldehyde and NAD+ are bound to the enzyme to facilitate catalysis. Based on the information obtained from this structural analysis and comparisons of specificities for the five enzymes that were characterized, correlations to the potential roles played by specific residues within the structure may be drawn.

Fatty aldehyde dehydrogenase, the enzyme downstream of tetrahydrobiopterin-dependent alkylglycerol monooxygenase

Pteridines ◽  
2013 ◽  
Vol 24 (1) ◽  
pp. 105-109 ◽  
Author(s):  
Markus A. Keller ◽  
Katrin Watschinger ◽  
Georg Golderer ◽  
Gabriele Werner-Felmayer ◽  
Ernst R. Werner
Keyword(s):  
Aldehyde Dehydrogenase ◽  
Treatment Options ◽  
Ether Lipid ◽  
Signalling Pathways ◽  
Fatty Aldehyde ◽  
Ether Lipids ◽  
Lipid Degradation ◽  
Physiological Importance ◽  
Fatty Aldehydes ◽  
Larsson Syndrome

AbstractThe tetrahydrobiopterin-dependent degradation of ether lipids by alkylglycerol monooxygenase (AGMO) produces fatty aldehydes, which are toxic to cells. Therefore, it is of great physiological importance that these harmful compounds are converted into their corresponding, less toxic fatty acids by fatty aldehyde dehydrogenase (FALDH). Dysfunction of this enzyme causes Sjögren-Larsson syndrome. This severe inherited disorder is accompanied by symptoms such as ichthyosis, mental retardation and spasticity. Surprisingly, fatty alcohols and not fatty aldehydes were found to accumulate in fibroblasts of Sjögren-Larsson syndrome patients, suggesting that there can be wide-ranging alterations in the lipid composition of patient cells. In particular, this has to be considered when searching for possible treatment options for patients suffering from Sjögren-Larsson syndrome. For example, inhibition of fatty aldehyde producing ether lipid degradation would have multiple implications on ether lipid- and fatty alcohol-mediated signalling pathways.

scholarly journals Aldehyde dehydrogenase in 2-acetaminofluorene-induced rat hepatomas. Ontogeny and evidence that the new isoenzymes are not due to normal gene de-repression

1977 ◽  
Vol 164 (1) ◽  
pp. 119-123 ◽  
Author(s):  
Ronald Lindahl
Keyword(s):  
Rat Liver ◽  
Aldehyde Dehydrogenase ◽  
Double Diffusion ◽  
Normal Liver ◽  
Normal Adult ◽  
Sprague Dawley ◽  
Adult Liver ◽  
Aldehyde Dehydrogenases ◽  
Adult Rat ◽  
Liver Aldehyde Dehydrogenase

The pre- and post-natal ontogeny of Sprague–Dawley rat liver aldehyde dehydrogenase [aldehyde–NAD(P)+ oxidoreductase, EC 1.2.1.5] is described. At no time in its ontogenetic development does normal liver aldehyde dehydrogenase exhibit any of the characteristics of a series of unique aldehyde dehydrogenases that can be isolated from 2-acetamidofluorene-induced rat hepatomas. Enzyme activity is first detectable in 15-day foetal liver and gradually increases throughout pre- and post-natal development until adult activities are attained by day 49 after birth. Electrophoretically, normal aldehyde dehydrogenase, throughout its ontogeny, exists as the same single isoenzyme found in normal adult liver. Isoelectric points for two normal liver isoenzymes demonstrable by isoelectric focusing are pH5.9 and 6.0. The immunochemical properties of aldehyde dehydrogenase during its ontogeny are identical with those of normal adult liver aldehyde dehydrogenase when tested against anti-(hepatoma aldehyde dehydrogenase) serum in Ouchterlony double-diffusion tests. The results indicate that the hepatoma-specific aldehyde dehydrogenases are not the result of the de-repression of genes normally repressed in adult rat liver or in some other adult tissue.

scholarly journals Two novel cyanobacterial α-dioxygenases for the biosynthesis of fatty aldehydes

2021 ◽  
Author(s):  
In Jung Kim ◽  
Yannik Brack ◽  
Thomas Bayer ◽  
Uwe T. Bornscheuer
Keyword(s):  
Fatty Acids ◽  
Functional Characterization ◽  
Fatty Aldehyde ◽  
Medium Carbon ◽  
E Coli ◽  
Industrial Utilization ◽  
Key Points ◽  
Plant Enzymes ◽  
Fatty Aldehydes ◽  
Fragrance Compounds

Abstractα-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 Graphical abstract

scholarly journals Effects of NAD+ in Caenorhabditis elegans Models of Neuronal Damage

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 993
Author(s):  
Yuri Lee ◽  
Hyeseon Jeong ◽  
Kyung Hwan Park ◽  
Kyung Won Kim
Keyword(s):  
Caenorhabditis Elegans ◽  
Therapeutic Strategy ◽  
Axon Regeneration ◽  
Neuronal Damage ◽  
Biological Processes ◽  
Nematode Caenorhabditis Elegans ◽  
C Elegans ◽  
Neuronal Functions ◽  
Molecular Components

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor that mediates numerous biological processes in all living cells. Multiple NAD+ biosynthetic enzymes and NAD+-consuming enzymes are involved in neuroprotection and axon regeneration. The nematode Caenorhabditis elegans has served as a model to study the neuronal role of NAD+ because many molecular components regulating NAD+ are highly conserved. This review focuses on recent findings using C. elegans models of neuronal damage pertaining to the neuronal functions of NAD+ and its precursors, including a neuroprotective role against excitotoxicity and axon degeneration as well as an inhibitory role in axon regeneration. The regulation of NAD+ levels could be a promising therapeutic strategy to counter many neurodegenerative diseases, as well as neurotoxin-induced and traumatic neuronal damage.

Kinetic properties of chimeric class I aldehyde dehydrogenases for retinal isomers

2006 ◽  
Vol 84 (5) ◽  
pp. 799-804
Author(s):  
Hélène Brodeur ◽  
Samuel Chagnon ◽  
Maxime Parisotto ◽  
Sylvie Mader ◽  
Pangala V. Bhat
Keyword(s):  
Aldehyde Dehydrogenase ◽  
Residual Activity ◽  
Kinetic Properties ◽  
Lower Efficiency ◽  
Aldehyde Dehydrogenases ◽  
Chimeric Enzymes ◽  
Retinoic Acids ◽  
Retinal Isomers

Retinal dehydrogenase type 1 (RALDH1) catalyzes the oxidation of all-trans and 9-cis retinal to the respective retinoic acids (RAs), whereas another member of the aldehyde dehydrogenase (ALDH) family, the phenobarbital-induced aldehyde dehydrogenase (PB-ALDH), is very poorly active. We have previously generated chimeras between these 2 enzymes that displayed selectivity for retinal isomers in crude bacterial extracts. Here we have characterized the kinetic properties of the corresponding purified recombinant proteins. The all-trans selective chimera RALDH-131 converted all-trans retinal to all-trans RA with 2.9-fold lower efficiency than the wild-type RALDH1 and had only residual activity with 9-cis retinal. The converse chimera PB-131 was specific for 9-cis retinal, with no residual activity for all-trans retinal. MgCl2 inhibited the activities of RALDH1 and PB-131, but not of RALDH-131, suggesting that amino acids 132–510 in RALDH are necessary for inhibition by MgCl2. These data demonstrate that the chimeric enzymes act as retinal isomer-selective ALDHs, and suggest that these enzymes may be useful to study the roles of cis RA isomers in embryogenesis and differentiation in vivo.

scholarly journals The activation of aldehyde dehydrogenase by diethylstilboestrol and 2,2′-dithiodipyridine

1982 ◽  
Vol 207 (1) ◽  
pp. 81-89 ◽  
Author(s):  
T M Kitson
Keyword(s):  
Enzyme Activity ◽  
Aldehyde Dehydrogenase ◽  
Human Liver ◽  
Common Property ◽  
Rabbit Liver ◽  
Aldehyde Dehydrogenases ◽  
Cytoplasmic Enzyme ◽  
Sheep Liver ◽  
Low Concentrations ◽  
Liver Aldehyde Dehydrogenase

1. The activation of sheep liver cytoplasmic aldehyde dehydrogenase by diethylstilboestrol and by 2,2′-dithiodipyridine is described. The effects of the two modifiers are very similar with respect to variation with acetaldehyde concentration, pH and temperature. Thus the degree of activation is maximal when the enzyme is assayed at approx. 1 mM-acetaldehyde, is greater at 25 degrees C than at 37 degrees C, and is greater at pH 7.4 than at pH 9.75. With low concentrations of acetaldehyde both modifiers decrease the enzyme activity. 2. Diethylstilboestrol affects the sheep liver cytoplasmic enzyme in a very similar way to that previously described for a rabbit liver cytoplasmic enzyme. Preliminary experiments show that the same is true for a preparation of human liver aldehyde dehydrogenase. It is proposed that sensitivity to diethylstilboestrol (and steroids) is a common property of all mammalian cytoplasmic aldehyde dehydrogenases.

Sign in / Sign up

Export Citation Format

Share Document