scholarly journals Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration

2015 ◽  
Vol 112 (42) ◽  
pp. 12962-12967 ◽  
Author(s):  
Lihong Zhao ◽  
Stefka Spassieva ◽  
Kenneth Gable ◽  
Sita D. Gupta ◽  
Lan-Ying Shi ◽  
...  
Keyword(s):  
Chain Length ◽  
Small Subunit ◽  
Fatty Acyl ◽  
Substrate Affinity ◽  
Serine Palmitoyltransferase ◽  
Membrane Structures ◽  
Long Chain Base ◽  
Chain Lengths ◽  
Long Chain

Sphingolipids typically have an 18-carbon (C18) sphingoid long chain base (LCB) backbone. Although sphingolipids with LCBs of other chain lengths have been identified, the functional significance of these low-abundance sphingolipids is unknown. The LCB chain length is determined by serine palmitoyltransferase (SPT) isoenzymes, which are trimeric proteins composed of two large subunits (SPTLC1 and SPTLC2 or SPTLC3) and a small subunit (SPTssa or SPTssb). Here we report the identification of an Sptssb mutation, Stellar (Stl), which increased the SPT affinity toward the C18 fatty acyl-CoA substrate by twofold and significantly elevated 20-carbon (C20) LCB production in the mutant mouse brain and eye, resulting in surprising neurodegenerative effects including aberrant membrane structures, accumulation of ubiquitinated proteins on membranes, and axon degeneration. Our work demonstrates that SPT small subunits play a major role in controlling SPT activity and substrate affinity, and in specifying sphingolipid LCB chain length in vivo. Moreover, our studies also suggest that excessive C20 LCBs or C20 LCB-containing sphingolipids impair protein homeostasis and neural functions.

scholarly journals Effect of long-chain fatty acyl-CoA on mitochondrial and cytosolic ATP/ADP ratios in the intact liver cell

1984 ◽  
Vol 220 (2) ◽  
pp. 371-376 ◽  
Author(s):  
S Soboll ◽  
H J Seitz ◽  
H Sies ◽  
B Ziegler ◽  
R Scholz
Keyword(s):  
Liver Cell ◽  
Adenine Nucleotide ◽  
Intact Cell ◽  
Inhibitory Effect ◽  
Fatty Acyl ◽  
Fed State ◽  
Physiological Relevance ◽  
Chain Acyl ◽  
Long Chain

The effect of long-chain acyl-CoA on subcellular adenine nucleotide systems was studied in the intact liver cell. Long-chain acyl-CoA content was varied by varying the nutritional state (fed and starved states) or by addition of oleate. Starvation led to an increase in the mitochondrial and a decrease in the cytosolic ATP/ADP ratio in liver both in vivo and in the isolated perfused organ as compared with the fed state. The changes were reversed on re-feeding glucose in liver in vivo or on infusion of substrates (glucose, glycerol) in the perfused liver, respectively. Similar changes in mitochondrial and cytosolic ATP/ADP ratios occurred on addition of oleate, but, importantly, not with a short-chain fatty acid such as octanoate. It is concluded that long-chain acyl-CoA exerts an inhibitory effect on mitochondrial adenine nucleotide translocation in the intact cell, as was previously postulated in the literature from data obtained with isolated mitochondria. The physiological relevance with respect to pyruvate metabolism, i.e. regulation of pyruvate carboxylase and pyruvate dehydrogenase by the mitochondrial ATP/ADP ratio, is discussed.

The Use of N-alkanes for Estimating Intake and Passage Rate in Horses

1996 ◽  
Vol 1996 ◽  
pp. 98-98
Author(s):  
B M L McLean ◽  
R W Mayes ◽  
F D DeB Hovell
Keyword(s):  
Recent Work ◽  
Chain Length ◽  
Carbon Chain ◽  
Carbon Chain Length ◽  
Passage Rate ◽  
Forage Crops ◽  
Carbon Chains ◽  
Naturally Occurring ◽  
Chain Lengths ◽  
Long Chain

Alkanes occur naturally in all plants, although forage crops tend to have higher alkane contents than cereals. N-alkanes have odd-numbered carbon chains. They are ideal for use as markers in feed trials, because, they are inert, indigestible and naturally occurring, and can be recovered in animal faeces. Synthetic alkanes (even-numbered carbon chains) are available commercially and can also used as external markers. Dove and Mayes (1991) cite evidence indicating that faecal recovery of alkanes in ruminants increases with increasing carbon-chain length. Thus the alkane “pairs” (e.g. C35 & C36, and C32 & C33) are used in calculating intake and digestibility because they are long chain and adjacent to each other. However, recent work by Cuddeford and Mayes (unpublished) has found that in horses the faecal recovery rates are similar regardless of chain lengths.

scholarly journals Candida albicans sphingolipid C9-methyltransferase is involved in hyphal elongation

Microbiology ◽  
2010 ◽  
Vol 156 (4) ◽  
pp. 1234-1243 ◽  
Author(s):  
Takahiro Oura ◽  
Susumu Kajiwara
Keyword(s):  
Candida Albicans ◽  
Lipid Membrane ◽  
Hyphal Growth ◽  
Pathogenic Fungi ◽  
Wild Type ◽  
Membrane Structures ◽  
Pathogenic Yeast ◽  
Chain Base ◽  
Long Chain Base ◽  
Long Chain

C9-methylated glucosylceramide is a fungus-specific sphingolipid. This lipid is a major membrane component in the cell and is thought to play important roles in the growth and virulence of several fungal species. To investigate the importance of the methyl branch of the long-chain base in glucosylceramides in pathogenic fungi, we identified and characterized a sphingolipid C9-methyltransferase gene (MTS1, C9-MethylTransferase for Sphingolipid 1) in the pathogenic yeast Candida albicans. The mts1 disruptant lacked (E,E)-9-methylsphinga-4,8-dienine in its glucosylceramides and contained (E)-sphing-4-enine and (E,E)-sphinga-4,8-dienine. Reintroducing the MTS1 gene into the mts1 disruptant restored the synthesis of (E,E)-9-methylsphinga-4,8-dienine in the glucosylceramides. We also created a disruptant of the HSX11 gene, encoding glucosylceramide synthase, which catalyses the final step of glucosylceramide synthesis, in C. albicans and compared this mutant with the mts1 disruptant. The C. albicans mts1 and hsx11 disruptants both had a decreased hyphal growth rate compared to the wild-type strain. The hsx11 disruptant showed increased susceptibility to SDS and fluconazole, similar to a previously reported sld1 disruptant that contained only (E)-sphing-4-enine in its glucosylceramides, suggesting that these strains have defects in their cell membrane structures. In contrast, the mts1 disruptant grew similarly to wild-type in medium containing SDS or fluconazole. These results suggest that the C9-methyl group of a long-chain base in glucosylceramides plays an important role in the hyphal elongation of C. albicans independent of lipid membrane disruption.

scholarly journals Subunit composition of the mammalian serine-palmitoyltransferase defines the spectrum of straight and methyl-branched long-chain bases

2020 ◽  
Vol 117 (27) ◽  
pp. 15591-15598 ◽  
Author(s):  
Museer A. Lone ◽  
Andreas J. Hülsmeier ◽  
Essa M. Saied ◽  
Gergely Karsai ◽  
Christoph Arenz ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Mammalian Cells ◽  
High Density Lipoproteins ◽  
Serine Palmitoyltransferase ◽  
Product Spectrum ◽  
Long Chain Base ◽  
The Individual ◽  
And Function ◽  
Long Chain

Sphingolipids (SLs) are chemically diverse lipids that have important structural and signaling functions within mammalian cells. SLs are commonly defined by the presence of a long-chain base (LCB) that is normally formed by the conjugation ofl-serine and palmitoyl-CoA. This pyridoxal 5-phosphate (PLP)-dependent reaction is mediated by the enzyme serine-palmitoyltransferase (SPT). However, SPT can also metabolize other acyl-CoAs, in the range of C14to C18, forming a variety of LCBs that differ by structure and function. Mammalian SPT consists of three core subunits: SPTLC1, SPTLC2, and SPTLC3. Whereas SPTLC1 and SPTLC2 are ubiquitously expressed, SPTLC3 expression is restricted to certain tissues only. The influence of the individual subunits on enzyme activity is not clear. Using cell models deficient in SPTLC1, SPTLC2, and SPTLC3, we investigated the role of each subunit on enzyme activity and the LCB product spectrum. We showed that SPTLC1 is essential for activity, whereas SPTLC2 and SPTLC3 are partly redundant but differ in their enzymatic properties. SPTLC1 in combination with SPTLC2 specifically formed C18, C19, and C20 LCBs while the combination of SPTLC1 and SPTLC3 yielded a broader product spectrum. We identifiedanteiso-branched-C18 SO (meC18SO) as the primary product of the SPTLC3 reaction. The meC18SO was synthesized fromanteiso-methyl-palmitate, in turn synthesized from a precursor metabolite generated in the isoleucine catabolic pathway. The meC18SO is metabolized to ceramides and complex SLs and is a constituent of human low- and high-density lipoproteins.

scholarly journals C. Elegans Fatty Acid Two-Hydroxylase Regulates Intestinal Homeostasis by Affecting Heptadecenoic Acid Production

2018 ◽  
Vol 49 (3) ◽  
pp. 947-960 ◽  
Author(s):  
Yuanbao Li ◽  
Chunxia Wang ◽  
Yikai Huang ◽  
Rong Fu ◽  
Hanxi Zheng ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Click Chemistry ◽  
Protein Transport ◽  
Lipid Analysis ◽  
Fatty Acyl ◽  
Intestinal Cells ◽  
Membrane Structures ◽  
C Elegans ◽  
Apical Side

Background/Aims: The hydroxylation of fatty acids at the C-2 position is the first step of fatty acid α-oxidation and generates sphingolipids containing 2-hydroxy fatty acyl moieties. Fatty acid 2-hydroxylation is catalyzed by Fatty acid 2-hydroxylase (FA2H) enzyme. However, the precise roles of FA2H and fatty acid 2-hydroxylation in whole cell homeostasis still remain unclear. Methods: Here we utilize Caenorhabditis elegans as the model and systemically investigate the physiological functions of FATH-1/C25A1.5, the highly conserved worm homolog for mammalian FA2H enzyme. Immunostaining, dye-staining and translational fusion reporters were used to visualize FATH-1 protein and a variety of subcellular structures. The “click chemistry” method was employed to label 2-OH fatty acid in vivo. Global and tissue-specific RNAi knockdown experiments were performed to inactivate FATH-1 function. Lipid analysis of the fath-1 deficient mutants was achieved by mass spectrometry. Results: C. elegans FATH-1 is expressed at most developmental stages and in most tissues. Loss of fath-1 expression results in severe growth retardation and shortened lifespan. FATH-1 function is crucially required in the intestine but not the epidermis with stereospecificity. The “click chemistry” labeling technique showed that the FATH-1 metabolites are mainly enriched in membrane structures preferable to the apical side of the intestinal cells. At the subcellular level, we found that loss of fath-1 expression inhibits lipid droplets formation, as well as selectively disrupts peroxisomes and apical endosomes. Lipid analysis of the fath-1 deficient animals revealed a significant reduction in the content of heptadecenoic acid, while other major FAs remain unaffected. Feeding of exogenous heptadecenoic acid (C17: 1), but not oleic acid (C18: 1), rescues the global and subcellular defects of fath-1 knockdown worms. Conclusion: Our study revealed that FATH-1 and its catalytic products are highly specific in the context of chirality, C-chain length, spatial distribution, as well as the types of cellular organelles they affect. Such an unexpected degree of specificity for the synthesis and functions of hydroxylated FAs helps to regulate protein transport and fat metabolism, therefore maintaining the cellular homeostasis of the intestinal cells. These findings may help our understanding of FA2H functions across species, and offer potential therapeutical targets for treating FA2H-related diseases.

scholarly journals Lipopolysaccharide O-Antigen Chain Length Regulation in Pseudomonas aeruginosa Serogroup O11 Strain PA103

2007 ◽  
Vol 190 (8) ◽  
pp. 2709-2716 ◽  
Author(s):  
Erica Kintz ◽  
Jennifer M. Scarff ◽  
Antonio DiGiandomenico ◽  
Joanna B. Goldberg
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Chain Length ◽  
Gene Mutations ◽  
Side Chain ◽  
Wild Type ◽  
O Antigen ◽  
Length Regulation ◽  
O Antigens ◽  
Chain Lengths ◽  
Long Chain

ABSTRACT The Wzz proteins are important for determining the length of the O-antigen side chain attached to lipopolysaccharide (LPS). Several bacteria, including Pseudomonas aeruginosa strain PAO1 (serogroup O5), produce two such proteins responsible for the preference of two different chain lengths on the surface. Our group has previously identified one wzz gene (wzz1) within the O-antigen locus of P. aeruginosa strain PA103 (serogroup O11). In this study we have identified the second wzz gene (wzz2), located in the same region of the genome and with 92% similarity to PAO1's wzz2 gene. Mutations were generated in both wzz genes by interruption with antibiotic resistance cassettes, and the effects of these mutations were characterized. Wild-type PA103 prefers two O-antigen chain lengths, referred to as long and very long. The expression of the long O-antigen chain length was reduced in the wzz1 mutant, indicating the Wzz1 protein is important for this chain length preference. The wzz2 mutant, on the other hand, was missing O-antigens of the very long chain length, indicating the Wzz2 protein is responsible for the production of very long O-antigen. The effects of the wzz mutations on virulence were also investigated. In both serum sensitivity assays and a mouse pneumonia model of infection, the wzz1 mutants exhibited greater defects in virulence compared to either wild-type PA103 or the wzz2 mutant, indicating the long chain length plays a greater role during these infectious processes.

scholarly journals Preparation of Bisphenol-A and Polydimethylsiloxane (PDMS) Block Copolycarbonates by Melt Polycondensation: Effects of PDMS Chain Length on Conversion and Miscibility

Polymers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 2660
Author(s):  
Zibo Zhou ◽  
Guozhang Wu
Keyword(s):  
Bisphenol A ◽  
Chain Length ◽  
Short Chain ◽  
Side Reactions ◽  
Diphenyl Carbonate ◽  
Key Factors ◽  
Factors Affecting ◽  
Melt Polycondensation ◽  
Chain Lengths ◽  
Long Chain

This study aimed to improve polydimethylsiloxane (PDMS) conversion in the preparation of polycarbonate (PC)–polydimethylsiloxane (PDMS) copolymer through melt polycondensation. We examined the transesterification process of PDMS with diphenyl carbonate (DPC) and its copolymerization products with bisphenol-A (BPA) for different chain lengths of PDMS. The key factors affecting PDMS conversion were investigated. Results showed that long-chain PDMS required a higher critical transesterification level (38.6%) to improve miscibility with DPC. During polycondensation, side reactions were more prone to occur when the equilibrium transesterification level of long-chain PDMS was lower. PDMS conversion was also lower when more short-chain PDMS was fed. Increasing the chain length of PDMS also reduced PDMS conversion. Notably, increasing the amount of KOH can significantly improve PDMS conversion throughout the polycondensation stage by increasing the equilibrium transesterification level of long-chain PDMS, thereby inhibiting the occurrence of side reactions.

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