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PubMed2004

Slr1293 in Synechocystis sp. strain PCC 6803 Is the C-3',4' desaturase (CrtD) involved in myxoxanthophyll biosynthesis.

When grown at high light intensity, more than a quarter of the total carotenoids in the unicellular cyanobacterium Synechocystis consists of myxoxanthophyll, a polar carotenoid glycoside. The biosynthetic pathway of myxoxanthophyll is unknown but is presumed to involve a number of enzymes, including a C-3',4' desaturase required to add one double bond to generate 11 conjugated double bonds in the monocyclic myxoxanthophyll. A candidate for this desaturase is Slr1293, which was identified by genome similarity searching. To determine whether Slr1293 is a desaturase recognizing neurosporene and lycopene, slr1293 was expressed in Escherichia coli strains accumulating neurosporene or lycopene. Confirming such a desaturase function for Slr1293, these E. coli strains accumulated 3',4'-didehydroneurosporene and 3',4'-didehydrolycopene, respectively. Indeed, deletion of slr1293 in Synechocystis provides further evidence that Slr1293 is a desaturase recognizing neurosporene: In the slr1293 deletion mutant, neurosporene was found to accumulate and was further processed to produce neurosporene glycoside. Neurosporene hereby becomes a primary candidate to be the branch point molecule between carotene and myxoxanthophyll biosynthesis in this cyanobacterium. The slr1293 gene was concluded to encode a C-3',4' desaturase that is essential for myxoxanthophyll biosynthesis, and thus it was designated as crtD. Furthermore, as Slr1293 appears to recognize neurosporene and to catalyze the first committed step on the myxoxanthophyll biosynthesis pathway, Slr1293 plays a pivotal role in directing a portion of the precursor pool for carotenoid biosynthesis toward myxoxanthophyll biosynthesis in Synechocystis sp. strain PCC 6803.

Bacterial Proteins↗

PubMed2003

NAD+-dependent deacetylase Hst1p controls biosynthesis and cellular NAD+ levels in Saccharomyces cerevisiae.

Nicotine adenine dinucleotide (NAD(+)) performs key roles in electron transport reactions, as a substrate for poly(ADP-ribose) polymerase and NAD(+)-dependent protein deacetylases. In the latter two processes, NAD(+) is consumed and converted to ADP-ribose and nicotinamide. NAD(+) levels can be maintained by regeneration of NAD(+) from nicotinamide via a salvage pathway or by de novo synthesis of NAD(+) from tryptophan. Both pathways are conserved from yeast to humans. We describe a critical role of the NAD(+)-dependent deacetylase Hst1p as a sensor of NAD(+) levels and regulator of NAD(+) biosynthesis. Using transcript arrays, we show that low NAD(+) states specifically induce the de novo NAD(+) biosynthesis genes while the genes in the salvage pathway remain unaffected. The NAD(+)-dependent deacetylase activity of Hst1p represses de novo NAD(+) biosynthesis genes in the absence of new protein synthesis, suggesting a direct effect. The known Hst1p binding partner, Sum1p, is present at promoters of highly inducible NAD(+) biosynthesis genes. The removal of HST1-mediated repression of the NAD(+) de novo biosynthesis pathway leads to increased cellular NAD(+) levels. Transcript array analysis shows that reduction in cellular NAD(+) levels preferentially affects Hst1p-regulated genes in comparison to genes regulated with other NAD(+)-dependent deacetylases (Sir2p, Hst2p, Hst3p, and Hst4p). In vitro experiments demonstrate that Hst1p has relatively low affinity toward NAD(+) in comparison to other NAD(+)-dependent enzymes. These findings suggest that Hst1p serves as a cellular NAD(+) sensor that monitors and regulates cellular NAD(+) levels.

Adenosine Diphosphate Ribose↗

PubMed2026

Genome-resolved analysis reveals disruption of gut microbial vitamin B and K2 biosynthesis during Toxoplasma gondii infection in mice.

UNLABELLED: Toxoplasma gondii infection remodels the gut microbiome, yet its impact on microbial vitamin biosynthetic potential and host redox metabolism remains unclear. Here, we integrated mouse gut metagenomes with publicly available metagenome-assembled genomes (MAGs) to construct a genome-resolved atlas of B-vitamin and vitamin K2 biosynthesis. From 45,697 MAGs, we curated 4,771 representative genomes, of which 2,682 met high-quality criteria (completeness ≥90%, contamination <5%). Functional annotation identified 229,717 vitamin-related genes corresponding to 177 Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologs across de novo pathways for eight B vitamins, thiamine (B1), riboflavin (B2), niacin (B3), pantothenate (B5), pyridoxine (B6), biotin (B7), folate (B9), cobalamin (B12), and vitamin K2. Among the high-quality genomes, 1,665 encoded complete de novo pathways for at least one vitamin, highlighting functional specialization and community-level complementarity. Transcripts per million-normalized metagenomic read counts revealed significant differences in KEGG ortholog abundances across six of the nine vitamin pathways. Reanalysis of metagenomic data from infected mice (acute, chronic, and control; n = 10 per group) revealed a stage-dependent reduction in α-diversity of vitamin biosynthesis pathways during acute infection, and a clear β-diversity separation from chronic and control groups. Core niacin biosynthesis genes (nadB, nadA, nadC) displayed phylum-specific redistribution, indicating selective remodeling of microbial NAD+ precursor production under infection-induced metabolic stress. These results suggest that T. gondii infection disrupts cooperative vitamin biosynthetic networks while specifically modulating niacin pathways linked to host NAD+ metabolism. IMPORTANCE: Gut microbes can synthesize essential vitamins, but how infection alters this function is poorly understood. By integrating mouse gut metagenomes with genome-resolved microbial data, we show that Toxoplasma gondii infection reshapes the vitamin biosynthetic potential of the gut microbiome in a stage-dependent manner. Acute infection reduces the diversity of vitamin biosynthesis pathways and shifts the taxonomic distribution of key niacin biosynthesis genes involved in microbial NAD+ precursor production. These findings identify vitamin metabolism, especially niacin-related pathways, as a sensitive functional axis of microbiome remodeling during infection. Our work links microbial taxonomic changes to functional metabolic consequences and suggests that microbiome-mediated regulation of NAD+-related metabolism may contribute to host redox adaptation during T. gondii infection.

B vitamins↗

PubMed2001

Effect of 5 alpha-pregnan-3 alpha-ol-20-one on nitric oxide biosynthesis and plasma volume in rats.

Plasma 5 alpha-pregnan-3 alpha-ol-20-one (pregnan) levels and nitric oxide (NO) biosynthesis increase during pregnancy. These factors have independently been implicated in the control of blood pressure and volume. We wished to determine whether pregnan might be responsible both for the increase in NO biosynthesis and for the increase in plasma volume observed during pregnancy. Virgin female Long-Evans rats were implanted with indwelling cannulas and maintained on a low nitrate/nitrite diet. After the rats recovered from surgery, 500 microg of pregnan or vehicle were given daily for 2 days. NO biosynthesis and plasma volume were measured in conscious animals before and after treatment. Pregnan caused a significant increase in NO biosynthesis (1.9 +/- 0.8 micromol/24 h, n = 10) compared with the vehicle-treated control group (0.3 +/- 0.4 micromol/24 h, n = 10, P < 0.05). Similarly, there was a significant increase in plasma volume in the pregnan-treated group (0.7 +/- 0.2 ml/100 g, n = 11) compared with the vehicle-treated control group (0.2 +/- 0.1 ml/100 g, n = 11, P < 0.05). These results confirm that pregnan can mimic pregnancy by its ability to increase both NO biosynthesis and plasma volume.

Animals↗

PubMed1984

Regulation of fatty acid biosynthesis in rats by physical training.

Physical training in the form of long-term nonexhaustive daily exercise was studied as a means of regulating fatty acid biosynthesis. Male rats were required to swim for periods up to 90 min/day. The exercise was carried out 6 days/wk for approximately 11 wk. Hepatic fatty acid biosynthesis and acetyl-CoA carboxylase [acetyl-CoA: CO2 ligase (EC 6.4.1.2)] activities were compared with nonexercised rats. At the end of the training period the exercised rats had a lower rate of fatty acid biosynthesis activity and a lower rate of acetyl-CoA carboxylase activity. The difference in acetyl-CoA carboxylase activity was due to a change in maximal velocity with no significant change in the Michaelis constant for acetyl-CoA. Untrained rats were subjected to a single bout of exercise. They also exhibited lower rates of fatty acid biosynthesis and acetyl-CoA carboxylase activities compared with nonexercised rats. However, the lower rates of these enzyme activities were sustained longer in the physically trained rats compared with the exercised untrained rats after the cessation of exercise. These results implicate acetyl-CoA carboxylase as a control site in the regulation of hepatic fatty acid biosynthesis by both physical training and acute exercise in rats. Possible inhibitory mechanisms are discussed.

Acetyl-CoA Carboxylase↗

PubMed2005

Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice.

Obstructive sleep apnea (OSA), a condition tightly linked to obesity, leads to chronic intermittent hypoxia (CIH) during sleep. There is emerging evidence that OSA is independently associated with insulin resistance and fatty liver disease, suggesting that OSA may affect hepatic lipid metabolism. To test this hypothesis, leptin-deficient obese (ob/ob) mice were exposed to CIH during the light phase (9 AM-9 PM) for 12 wk. Liver lipid content and gene expression profile in the liver (Affymetrix 430 GeneChip with real-time PCR validation) were determined on completion of the exposure. CIH caused a 30% increase in triglyceride and phospholipid liver content (P < 0.05), whereas liver cholesterol content was unchanged. Gene expression analysis showed that CIH upregulated multiple genes controlling 1) cholesterol and fatty acid biosynthesis [malic enzyme and acetyl coenzyme A (CoA) synthetase], 2) predominantly fatty acid biosynthesis (acetyl-CoA carboxylase and stearoyl-CoA desaturases 1 and 2), and 3) triglyceride and phospholipid biosynthesis (mitochondrial glycerol-3-phosphate acyltransferase). A majority of overexpressed genes were transcriptionally regulated by sterol regulatory element-binding protein (SREBP) 1, a master regulator of lipogenesis. A 2.8-fold increase in SREBP-1 gene expression in CIH was confirmed by real-time PCR (P = 0.001). Expression of major genes of cholesterol biosynthesis, SREBP-2 and 3-hydroxy-3-methylglutaryl-CoA reductase, was unchanged. In conclusion, we have shown that CIH may exacerbate preexisting fatty liver of obesity via upregulation of the pathways of lipid biosynthesis in the liver.

Animals↗

PubMed2005

Biosynthesis pathways for deoxysugars in antibiotic-producing actinomycetes: isolation, characterization and generation of novel glycosylated derivatives.

Many bioactive natural products synthesized by actinomycetes are glycosylated compounds in which the appended sugars contribute to specific interactions with their biological target. Most of these sugars are 6-deoxyhexoses, of which more than 70 different forms have been identified, and an increasing number of gene clusters involved in 6-deoxyhexoses biosynthesis are being characterized from antibiotic-producing actinomycetes. Novel glycosylated compounds have been generated by modifying natural deoxysugar biosynthesis pathways in the producer organisms, and/or the simultaneous expression in these strains of selected deoxysugar biosynthesis genes from other strains. Non-producing strains endowed with the capacity to synthesize novel deoxysugars through the expression of engineered deoxysugar biosynthesis clusters can also be used as alternative hosts. Transfer of these deoxysugars to a multiplicity of aglycones relies upon the existence of glycosyltransferases with an inherent degree of 'relaxed substrate specificity'. In this review, we analyze how the knowledge coming out from isolation and characterization of deoxysugar biosynthesis pathways from actinomycetes is being used to produce novel glycosylated derivatives of natural products.

Actinobacteria↗

PubMed2002

Angiotensin II induces tumor necrosis factor biosynthesis in the adult mammalian heart through a protein kinase C-dependent pathway.

BACKGROUND: Previous studies suggest that angiotensin II (Ang II) upregulates the expression of tumor necrosis factor (TNF) in nonmyocyte cell types; however, the effect of Ang II on TNF expression in the adult mammalian heart is not known. METHODS AND RESULTS: To determine whether Ang II was sufficient to provoke TNF biosynthesis in the adult heart, we examined the effects of Ang II in isolated buffer-perfused Langendorff feline hearts. Ang II (10(-7) mol/L) treatment resulted in a time- and dose-dependent increase in myocardial TNF mRNA and protein biosynthesis in the heart as well as in cultured adult cardiac myocytes. The effects of Ang II on myocardial TNF mRNA and protein synthesis were mediated through the angiotensin type 1 receptor (AT1R), insofar as an AT1R antagonist (AT1a) blocked the effects of Ang II, whereas an angiotensin type 2 receptor (AT2R) antagonist (AT2a) had no effect. Stimulation with Ang II led to the activation of nuclear factor-kappaB and activator protein-1 (AP-1), two transcription factors that are important for TNF gene expression. Nuclear factor-kappaB activation was accompanied by phosphorylation of IkappaBalpha on serine 32 as well as degradation of IkappaBalpha, suggesting that the effects of Ang II were mediated through an IkappaBalpha-dependent pathway. The important role of protein kinase C (PKC) was suggested by studies in which a phorbol ester triggered TNF biosynthesis, and a PKC inhibitor abrogated Ang II-induced TNF biosynthesis. CONCLUSIONS: These studies suggest that Ang II provokes TNF biosynthesis in the adult mammalian heart through a PKC-dependent pathway.

Angiotensin II↗

PubMed2000

Matrix-associated transforming growth factor-beta1 primes mouse bone marrow-derived mast cells for increased high-affinity Fc receptor for immunoglobulin E-dependent eicosanoid biosynthesis.

Mast cells at different tissue locations are heterogeneous with respect to histochemical staining characteristics, granule protease and proteoglycan content, and eicosanoid biosynthesis. We used Matrigel, an extract from the Engelbreth-Holm-Swarm mouse sarcoma that is enriched in basement-membrane proteins, to investigate the effect of tissue matrix proteins on the differentiation of mouse mast cells, with particular attention to eicosanoid biosynthesis. Culture of mouse bone-marrow cells in interleukin-3 on Matrigel for 3 to 4 wk provided a population of mast cells with more intense metachromasia and increased safranin counterstaining compared with mast cells derived in the absence of Matrigel (bone marrow-derived mast cells [BMMC]). High-affinity Fc receptor for immunoglobulin E-dependent biosynthesis of prostaglandin D(2) and leukotriene (LT) C(4) was 6- and 11-fold higher, respectively, from mast cells derived in the presence of Matrigel compared with conventional BMMC derived in its absence. BMMC derived in the presence of Matrigel also generated substantial quantities of 6-trans-LTB(4) diastereoisomers and LTB(4), which were minimally generated by conventional BMMC. When conventional BMMC derived in the absence of Matrigel were then cultured on Matrigel for 5 d, eicosanoid biosynthesis was upregulated without any change in granule staining characteristics. This upregulation in eicosanoid biosynthesis was inhibited by neutralizing anti- transforming growth factor (TGF)-beta1-specific antibodies, was reproduced by 1 ng/ml TGF-beta1, and was attributed to increased expression of cytosolic phospholipase A(2).

Animals↗

PubMed1989

Regulation of phosphatidylcholine biosynthesis in activated alveolar type II cells.

The biosynthesis of phosphatidylcholine was studied in a population of activated Type II cells isolated from the lungs of rats treated with silica. Type II cells were separated by centrifugal elutriation into two populations, designated Type IIA and Type IIB. The Type IIB or activated population consisted of Type II cells that were larger than normal cells; Type IIA cells were morphologically similar to normal Type II cells. Type IIB cells incorporated more [Me-14C]choline into both total phosphatidylcholine and disaturated phosphatidylcholine than did Type IIA or control Type II cells. Measurement of the pool sizes of the choline-containing precursors to phosphatidylcholine indicated that the biosynthesis of phosphatidylcholine was increased 4- to 5-fold in Type IIB cells. Increased conversion of cholinephosphate to CDP-choline was associated with increased phosphatidylcholine biosynthesis in Type IIB cells. Cholinephosphate cytidylyltransferase activity was increased approximately threefold in Type IIB cells. Subcellular fractionation indicated that essentially all of the increase in cytidylyltransferase activity was associated with the particulate fraction (100,000 x g pellet). In Type IIB cells, the particulate fraction contained 83% of the total cellular cytidylyltransferase activity; in control cells, this fraction contained 67% of the total activity. The specific activity of the cytidylyltransferase associated with the particulate fraction was increased twofold in Type IIB cells. The specific activity of the cytosolic enzyme was similar to that in control cells. Cholinephosphotransferase specific activity was increased approximately twofold in the activated Type II cells. The specific activity of choline kinase was the same as that in control Type II cells. These results demonstrate that the increased biosynthesis of phosphatidylcholine in Type IIB cells is a result of stimulation of the CDP-choline pathway. This study indicates that both cholinephosphate cytidylyltransferase and cholinephosphotransferase may be involved in regulating the de novo biosynthesis of phosphatidylcholine in alveolar Type II cells.

Animals↗

PubMed1977

Prostaglandin biosynthesis by rabbit renomedullary interstitial cells in tissue culture. Stimulation by angiotensin II, bradykinin, and arginine vasopressin.

Rabbit renomedullary interstitial cells were isolated and grown in tissue culture. These cells synthesize 0.8 ng of prostaglandin E2 (PGE2) per microgram cellular protein per hour in monolayer tissue culture; prostaglandins A2 and F2alpha (PGA2 and PGF2alpha) biosynthesis was 10 and 5% of PGE2 biosynthesis, respectively. Arachidonic acid markedly stimulated the production of PGE2 and PGF2alpha, with conversion rates of 0.24 and 0.02%/h, respectively. Angiotensin II, hyperosmolality, bradykinin, and arginine vasopressin each stimulated PGE2 biosynthesis; maximum stimulation was 20, 3.7, 3.6, and 3.2 times basal production, respectively. PGE2 biosynthesis by the renomedullary interstitial cells was inhibited by isoproterenol, potassium, nonsteroidal anti-inflammatory agents (indomethacin, naproxen, ibuprofen, suprofen, meclofenamate, and acetylsalicylic acid), mepacrine (a phospholipase inhibitor), hydrocortisone, and cortisone. The rabbit renomedullary interstitial cell in tissue culture is a model system for the study of hormonal regulation of PGE2 biosynthesis.

Angiotensin II↗

PubMed1981

Basis for the control of purine biosynthesis by purine ribonucleotides.

An animal model was used to determine the basis for the increase in purine biosynthesis that results from hepatic depletion of purine nucleotides, such as seen in patients with type I glycogen storage disease or following fructose administration. Mice were injected intravenously with glucose or fructose, 2.5 mg/g of body weight, and the animals were killed at 0, 3, and 30 min following carbohydrate infusion. Fructose, but not glucose, administration led to a threefold increase in [14C]glycine incorporation into hepatic purine nucleotides documenting an increase in the rate of purine biosynthesis in the liver of fructose-treated animals. In the fructose, but not the glucose-treated animals, there was a reduction in the hepatic content of purine nucleotides that are inhibitory for amidophosphoribosyltransferase, the enzyme that catalyzes the first reaction unique to the pathway of purine biosynthesis. PP-ribose-P, an important metabolite in the control of purine biosynthesis, was increased 2,3-fold in liver following fructose, but not glucose administration. In conjunction with the decrease in inhibitory nucleotides and increase in PP-ribose-P 29% of amidophosphoribosyltransferase was shifted from the large inactive to the small active form of the enzyme. Results of these studies demonstrate that the end-products of the pathway, purine nucleotides, control the activity of the enzyme that catalyzes the first reaction leading to purine nucleotide synthesis either through a direct effect of purine nucleotides on the enzyme, through an indirect effect of the change in nucleotides on PP-ribose-P synthesis, or a combination of these effects. The resultant changes in amidophosphoribosyltransferase conformation and activity provide a basis for understanding the increase in purine biosynthesis that results from hepatic depletion of purine nucleotides.

Amidophosphoribosyltransferase↗

PubMed1985

Insulin receptor biosynthesis in cultured lymphocytes from insulin-resistant patients.

In some patients with genetic forms of extreme insulin resistance, the cause of insulin resistance is a marked (greater than or equal to 90%) reduction in the number of insulin receptors on the cell surface. In the present work, we describe studies of insulin receptor biosynthesis in Epstein-Barr virus (EBV)-transformed lymphocytes from three patients (A-1, A-5, and A-8) with type A extreme insulin resistance. Insulin receptors are composed of two major glycoprotein subunits (apparent molecular weight [Mr] of 135 and 95 kD), which are both derived from a common precursor molecule with Mr of 190 kD. In one patient (A-1), there was a marked reduction in the biosynthesis of both the 190-kD precursor and the mature receptor. Thus, in this patient, the defect appears to occur early in the biosynthetic pathway (i.e., before the synthesis of the 190-kD precursor). In contrast, in two sisters (A-5 and A-8) with type A extreme insulin resistance, biosynthesis of the 190-kD precursor proceeds at a normal rate. However, there appears to be a defect subsequent to the biosynthesis of the 190-kD precursor, but before the insertion of the mature receptor in the plasma membrane. Our observations suggest the existence of at least two distinct types of biosynthetic defects which may give rise to a marked reduction in the number of insulin receptors on the cell surface. In addition, for comparison, we have studied receptor biosynthesis in cultured EBV lymphocytes from a fourth patient (A-7) with type A extreme insulin resistance. Although the cells of patient A-7 have a normal number of insulin receptors, we have detected subtle abnormalities in the posttranslational processing of the insulin receptor precursor, which may be a biochemical marker for a postbinding defect that causes insulin resistance in this patient.

Cells, Cultured↗

PubMed2006

Reduced thromboxane biosynthesis in carriers of toll-like receptor 4 polymorphisms in vivo.

The recent demonstration that platelets express a functional toll-like receptor 4 (TLR4) prompted us to explore the influence of TLR4 polymorphisms (Asp299Gly alone or in combination with Thr399Ile) on thromboxane A(2) (TXA(2)) biosynthesis in vivo. In 17 subjects with TLR4 polymorphisms versus 17 wild type (untreated with aspirin, matched for age, sex, and cardiovascular risk factors), intima-media thickness in the common carotid arteries was significantly lower. Average urinary excretion of 11-dehydro-TXB(2), an index of systemic biosynthesis of TX, was significantly reduced by 65%. The urinary excretion of 2,3-dinor-6-keto-prostaglandin F(1alpha), an index of systemic biosynthesis of prostacyclin, was marginally depressed but the prostacyclin/TXA(2) biosynthesis ratio was significantly higher than in wild type. Selective inhibition of cyclooxygenase 2-dependent prostacyclin (by rofecoxib or etoricoxib) was associated with increased urinary excretion of 11-dehydro-TXB(2) in carriers of TLR4 polymorphisms, but not in wild-type, suggesting a restrainable effect of prostacyclin on platelet function in vivo in this setting. Reduced TXA(2) biosynthesis may contribute to the protective cardiovascular phenotype of TLR4 polymorphisms.

Cardiovascular Diseases↗

PubMed2005

Differential effects of IL-10 on prostaglandin H synthase-2 expression and prostaglandin E2 biosynthesis between spleen and bone marrow macrophages.

Different populations of mononuclear phagocytes (MO) show considerable diversity of cellular function including prostaglandin E2 (PGE2) biosynthesis. Certain bacterial components enhance PGE2 biosynthesis differentially in selected populations of MO. Interleukin (IL)-10 is proposed to inhibit modulation of PGE2 biosynthesis by down-regulating prostaglandin G/H synthase-2 (PGHS-2) expression. To assess whether IL-10 regulates PGE2 biosynthesis and PGHS-2 expression, splenic and bone marrow MO were isolated from IL-10-deficient (IL-10(-/-)), C57Bl/6 [wild-type (WT) control], and Balb/c (comparison control) mice and were treated with lipopolysaccharide (LPS) and/or interferon-gamma (IFN-gamma) as a model of bacterial inflammation. LPS-induced PGHS-2 expression was similar for splenic MO isolated from the three strains of mice. However, PGE2 released by LPS-treated splenic MO was significantly higher in IL-10(-/-) and Balb/c than in WT cells. In the presence of LPS and IFN-gamma, PGHS-2 expression and PGE2 release by IL-10(-/-) and Balb/c splenic MO were enhanced compared with stimulation with LPS alone or IFN-gamma alone. However, there was no significant increase in PGE2 release from WT splenic MO treated with LPS plus IFN-gamma despite increased PGHS-2 expression. In sharp contrast, PGHS-2 expression and PGE2 release by bone marrow MO were greatly enhanced in IL-10(-/-) cells compared with control cells. Our results indicate that IL-10 regulation of MO PGE2 biosynthesis and PGHS-2 expression is compartment-dependent and that PGE2 production is not linked directly to PGHS-2 levels. Furthermore, our findings emphasize strain-specific differences between C57Bl/6 and Balb/c mice, and Balb/c appears more similar to the IL-10(-/-) than to the C57Bl/6 with respect to prostanoid production.

Animals↗

PubMed2004

Regulation of ganglioside biosynthesis in the nervous system.

Ganglioside biosynthesis is strictly regulated by the activities of glycosyltransferases and is necessarily controlled at the levels of gene transcription and posttranslational modification. Cells can switch between expressing simple and complex gangliosides or between different series within these two groups during brain development. The sequential biosynthesis of gangliosides in parallel enzymatic pathways, however, requires fine-tuned subcellular sequestration and orchestration of glycosyltransferases. A popular model predicts that this regulation is achieved by the vectorial organization of ganglioside biosynthesis: sequential biosynthetic steps occur with the traffic of ganglioside intermediates through subsequent subcellular compartments. Here, we review current models for the subcellular distribution of glycosyltransferases and discuss results that suggest a critical role of N-glycosylation for the processing, transport, and complex formation of these enzymes. In this context, we attempt to illustrate the regulation of ganglioside biosynthesis as well as the biological significance of N-glycosylation as a posttranslational regulatory mechanism. We also review the results of analyses of the 5' regulatory sequences of several glycosyltransferases in ganglioside biosynthesis and provide insights into how their synthesis can be regulated at the level of transcription.

Animals↗

PubMed1992

Increased biosynthesis of vasoactive prostanoids in Schönlein-Henoch purpura.

Schönlein-Henoch purpura (SHP) is an acute immune-mediated vasculitis characterized by infiltration of polymorphonuclear leukocytes into the vessel wall causing damage to the vascular endothelium by the release of proteolytic enzymes. The local inflammatory and thrombotic process may be regulated by increased biosynthesis of vasoactive prostanoids. We investigated the biosynthesis of thromboxane A2 (TxA2), a potent vasoconstrictor and platelet agonist, prostacyclin (PGI2), a vasodilator and platelet antagonist, and prostaglandin E2, a mediator of inflammation, in 14 children with SHP by physicochemical analysis of index metabolites in plasma and urine. TxA2 and PGI2 biosynthesis in the systemic circulation was significantly elevated in the acute phase of the disease and correlated with the degree of clinical symptoms. Recurrent episodes of the disease were associated with phasic increases of plasma and urinary TxA2 and PGI2 metabolites. Renal TxA2 formation was highest in two patients presenting with the nephrotic syndrome and extracapillary glomerulonephritis. Prostaglandin E2 biosynthesis in the systemic circulation was increased in the acute phase of the disease. The enhanced TxA2 formation is consistent with phasic platelet activation in SHP. The increased PGI2 biosynthesis reflects endothelial cell damage and may be a response of vascular endothelium to modulate platelet-vessel wall and leukocyte-vessel wall interactions. Increased prostaglandin E2 formation, which probably derives from activated polymorphonuclear leukocytes and macrophages, is thought to be related to the inflammatory process in SHP.

Adolescent↗

PubMed2005

Cyclooxygenase-2 regulation of the age-related decline in testosterone biosynthesis.

The age-related decline in testosterone biosynthesis in testicular Leydig cells has been well documented, but the mechanisms involved in the decline are not clear. Recent studies have described a cyclooxygenase-2 (COX2)-dependent tonic inhibition of Leydig cell steroidogenesis and expression of the steroidogenic acute regulatory protein (StAR). The present study was conducted to determine whether COX2 protein increases with age in rat Leydig cells and whether COX2 plays a role in the age-related decline in testosterone biosynthesis. Our results indicate that from 3 months of age to 30 months, COX2 protein in aged rat Leydig cells increased by 346% over that of young Leydig cells, StAR protein decreased to 33%, and blood testosterone concentration and testosterone biosynthesis in Leydig cells decreased to 41 and 33%, respectively. Further experiments demonstrated that overexpressing COX2 in MA-10 mouse Leydig cells inhibited StAR gene expression and steroidogenesis and that the inhibitory effects of COX2 could be reversed by blocking COX2 activity. Notably, incubation of aged Leydig cells with the COX2 inhibitor NS398 enhanced their testosterone biosynthesis. Blood testosterone concentrations in aged rats fed the COX2 inhibitor DFU, at doses of 5, 10, 15, and 20 mg/kg body weight per day were increased by 15, 23, 56, and 120%, respectively, over the levels in the rats receiving no DFU. The present study suggests a novel mechanism in male aging involving COX2 and a potential application of the mechanism to delay the age-related decline in testosterone biosynthesis.

Aging↗