Cyclophosphamide-impaired regulation of hepatic heme metabolism

Summary Im male rats hepatic cytochromes b₅ and P-450 were reduced at different times after treatment with cyclophosphamide (CP) (200 mg/kg i.p. for 3 days). In contrast, microsomal heme did not change until 48 h after the last dose of CP, leading to accumulation of heme in a non-cytochromal form. Parallel to the above changes the heme metabolism showed derangement: -aminolaevulinate synthase, the rate-limiting enzyme in heme synthesis, was depressed and heme oxygenase, the enzyme which catalyzes the oxidative degradation of heme, was increased.     

Biosynthesis of isoprenoids via the non-mevalonate pathway

The mevalonate pathway for the biosynthesis of the universal terpenoid precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), is known in considerable detail. Only recently, the existence of a second mevalonate-independent pathway for the biosynthesis of IPP and DMAPP was detected in plants and certain eubacteria. Experiments with ¹³C and/or ²H-labelled precursors were crucial in the elucidation of this novel route. The pathway is essential in plants, many eubacteria and apicomplexan parasites, but not in archaea and animals. The genes, enzymes and intermediates of this pathway were rapidly unravelled over the past few years. Detailed knowledge about the mechanisms of this novel route may benefit the development of novel antibiotics, antimalarials and herbicides.Received 7 October 2003; received after revision 23 December 2003; accepted 21 January 2004     

Turning points in the evolution of peroxidase–catalase superfamily: molecular phylogeny of hybrid heme peroxidases

Heme peroxidases and catalases are key enzymes of hydrogen peroxide metabolism and signaling. Here, the reconstruction of the molecular evolution of the peroxidase–catalase superfamily (annotated in pfam as PF00141) based on experimentally verified as well as numerous newly available genomic sequences is presented. The robust phylogenetic tree of this large enzyme superfamily was obtained from 490 full-length protein sequences. Besides already well-known families of heme b peroxidases arranged in three main structural classes, completely new (hybrid type) peroxidase families are described being located at the border of these classes as well as forming (so far missing) links between them. Hybrid-type A peroxidases represent a minor eukaryotic subfamily from Excavates, Stramenopiles and Rhizaria sharing enzymatic and structural features of ascorbate and cytochrome c peroxidases. Hybrid-type B peroxidases are shown to be spread exclusively among various fungi and evolved in parallel with peroxidases in land plants. In some ascomycetous hybrid-type B peroxidases, the peroxidase domain is fused to a carbohydrate binding (WSC) domain. Both here described hybrid-type peroxidase families represent important turning points in the complex evolution of the whole peroxidase–catalase superfamily. We present and discuss their phylogeny, sequence signatures and putative biological function.     

Cimetidine induces hepatic heme oxygenase activity without altering hepatic heme catabolism

Summary Cimetidine inhibits oxidative drug metabolism; it is not known whether this drug alters the catabolic fate of hepatic heme. We therefore investigated hepatic heme turnover both by a¹⁴CO breath test and directly by labeling the heme pool. Neither acute (150 mg/kg i.p.) nor chronic (150 mg/kg i.p. bid for 3 days) cimetidine administration significantly affected hepatic heme turnover. Chronic, but not acute, cimetidine significantly (p<0.025) increased heme oxygenase activity. Cimetidine inhibited heme oxygenase activity in vitro at concentrations achieved in vivo.     

Announcement of the Editor-in-Chief

Announcement.  As decided in July 2005 we continue to publish once a year (in July) the names of the authors and the titles of the two most read (by Internet) Research Papers and Reviews published in Cell. Mol. Life Sci. the previous year. Thus we have the pleasure to provide you with the results of 2005. Research Articles  

Biochemistry of the non-mevalonate isoprenoid pathway

The non-mevalonate pathway of isoprenoid (terpenoid) biosynthesis is essential in many eubacteria including the major human pathogen, Mycobacterium tuberculosis, in apicomplexan protozoa including the Plasmodium spp. causing malaria, and in the plastids of plants. The metabolic route is absent in humans and is therefore qualified as a promising target for new anti-infective drugs and herbicides. Biochemical and structural knowledge about all enzymes involved in the pathway established the basis for discovery and development of inhibitors by high-throughput screening of compound libraries and/or structure-based rational design.     

Composition du suc de décongélation du muscle strié de la grenouille

Summary Because of cell membrane destruction, fluid escaping a muscle on thawing contains a large amount of proteins (myogen and globulin X). Whilst usual gradientsa, b, andc are present in the fluid, the gradientsd ande also occurring in extracts of unstimulated frog muscles are replaced by the gradientx already found in extracts of in N₂ exhausted muscles.     

The superoxide-generating NADPH oxidase: structural aspects and activation mechanism

Flavocytochrome b ₅₅₈ is the catalytic core of the respiratory-burst oxidase, an enzyme complex that catalyzes the NADPH-dependent reduction of O₂ into the superoxide anion O₂ ^- in phagocytic cells. Flavocytochrome b ₅₅₈ is anchored in the plasma membrane. It is a heterodimer that consists of a large glycoprotein gp91phox (phox for phagocyte oxidase) (β subunit) and a small protein p22phox (α subunit). The other components of the respiratory-burst oxidase are water-soluble proteins of cytosolic origin, namely p67phox, p47phox, p40phox and Rac. Upon cell stimulation, they assemble with the membrane-bound flavocytochrome b ₅₅₈ which becomes activated and generates O₂ ^-. A defect in any of the genes encoding gp91phox, p22phox, p67phox or p47phox results in chronic granulomatous disease, a genetic disorder characterized by severe and recurrent infections, illustrating the role of O₂ ^- and the derived metabolites H₂O₂ and HOCl in host defense against invading microorganisms. The electron carriers, FAD and hemes b, and the binding site for NADPH are confined to the gp91phox subunit of flavocytochrome b ₅₅₈ . The p22phox subunit serves as a docking site for the cytosolic phox proteins. This review provides an overview of current knowledge on the structural organization of the O₂ ^--generating flavocytochrome b ₅₅₈ , its kinetics, its mechanism of activation and the regulation of its biosynthesis. Homologues of gp91phox, called Nox and Duox, are present in a large variety of non-phagocytic cells. They exhibit modest O₂ ^--generating oxidase activity, and some act as proton channels. Their role in various aspects of signal transduction is currently under investigation and is briefly discussed. Received 28 May 2002; received after revision 20 June 2002; accepted 24 June 2002     

Bacterial serine proteases secreted by the autotransporter pathway: classification,specificity, and role in virulence

Serine proteases exist in eukaryotic and prokaryotic organisms and have emerged during evolution as the most abundant and functionally diverse group. In Gram-negative bacteria, there is a growing family of high molecular weight serine proteases secreted to the external milieu by a fascinating and widely employed bacterial secretion mechanism, known as the autotransporter pathway. They were initially found in Neisseria, Shigella, and pathogenic Escherichia coli, but have now also been identified in Citrobacter rodentium, Salmonella, and Edwardsiella species. Here, we focus on proteins belonging to the serine protease autotransporter of Enterobacteriaceae (SPATEs) family. Recent findings regarding the predilection of serine proteases to host intracellular or extracellular protein-substrates involved in numerous biological functions, such as those implicated in cytoskeleton stability, autophagy or innate and adaptive immunity, have helped provide a better understanding of SPATEs’ contributions in pathogenesis. Here, we discuss their classification, substrate specificity, and potential roles in pathogenesis.     

The effect of hypoxia on hepatic cytochromes and heme turnover in rats in vivo

Summary We evaluated the effect of hypoxia (7% v/v) on hepatic heme turnover in vivo and microsomal heme protein content in male Sprague-Dawley rats. Hepatic heme protein turnover, measured as¹⁴CO-production during continuous infusion of 5-¹⁴C-aminolevulinic acid, a precursor of nonerythrogenic heme, was decreased 60% during hypoxia and returned to control levels promptly after reoxygenation. Hepatic cytochrome P-450 content was decreased in hypoxic and 24-h reoxygenated animals. We conclude that normobaric hypoxia decreases hepatic cytochrome P-450 which could contribute to decreased drug metabolism in hypoxia. This decrease is probably due to heme oxygenase-independent breakdown of hepatic heme.     

ARFIMA approximation and forecasting of the limiting aggregate structure of long‐memory process

This article studies Man and Tiao's (2006) low‐order autoregressive fractionally integrated moving‐average (ARFIMA) approximation to Tsai and Chan's (2005b) limiting aggregate structure of the long‐memory process. In matching the autocorrelations, we demonstrate that the approximation works well, especially for larger d values. In computing autocorrelations over long lags for larger d value, using the exact formula one might encounter numerical problems. The use of the ARFIMA(0, d, d?₁) model provides a useful alternative to compute the autocorrelations as a really close approximation. In forecasting future aggregates, we demonstrate the close performance of using the ARFIMA(0, d, d?₁) model and the exact aggregate structure. In practice, this provides a justification for the use of a low‐order ARFIMA model in predicting future aggregates of long‐memory process. Copyright © 2008 John Wiley & Sons, Ltd.     

Chemical defense in the three European species ofCrematogaster ants

The composition of the Dufour gland of the antC. scutellaris has been reinvestigated by gas chromatography/mass spectrometry. The major components of the gland are (2E,5E,12Z)-4-oxoheneicosa-2,5,12-trien-1-ol acetate (1a) its ¹⁴ and ¹⁶ double bond isomers (1b and1c), and the corresponding (Z,Z)-dienes5a and5b, all containing an acetylated C₂₁ chain. The previously proposed structures1d, 1e, and5c, which are based on an homologous acetylated C₂₃ chain, correspond to minor derivatives present in the gland. Traces of acetylated C₁₉ homologs, tentatively identified as1g-1i, have also been found. The Dufour gland contents of the two other EuropeanCrematogaster species have also been studied.C. auberti is very similar toC. scutellaris in producing mainly1a, 1b and1c, together with the same higher and lower homologs, but it lacks the dienic derivatives5, whereasC. sordidula contains essentially the acetylated C₁₉ compounds1g, 1h, and1i, accompanied by acetylated C₁₇ homologs.     

Influence of castration and testosterone replacement on hypothalamic tyrosine hydroxylase activity in the rat

Summary Hypothalamic tyrosine hydroxylase (TH) activity of castrate rats is modulated by testosterone propionate (TP) in vivo. Kinetic studies revealed that bothV _max andK _m were virtually unaltered for substrate tyrosine in the presence of an excess of DMPH₄ cofactor. TP replacement to castrate rats increased theK _m for added DMPH₄ cofactor, whileV _max decreased. These results suggest that TP decreases TH activity of castrate rats by inhibiting the enzymereduced pteridine cofactor complex.     

Forecasting for the generation of trading signals in financial markets

In this paper we show that optimal trading results can be achieved if we can forecast a key summary statistic of future prices. Consider the following optimization problem. Let the return r_i (over time i=1, 2, ..., n) for the ith day be given and the investor has to make investment decision d_i on the ith day with d_i=1 representing a ‘long' position and d_i=0 a ‘neutral' position. The investment return is given by r=Σⁿ_i=1r_id_i−cΣⁿ⁺¹_i=1∣d_i−d_i−1∣, where c is the transaction cost. The mathematical programming problem of choosing d₁, ..., d_n to maximize r under a given transaction cost c is shown to have an analytic solution, which is a function of a key summary statistic called the largest change before reversal. The largest change before reversal is recommended to be used as an output in a neural network for the generation of trading signals. When neural network forecasting is applied to a dataset of Hang Seng Index Futures Contract traded in Hong Kong, it is shown that forecasting the largest change before reversal outperforms the k‐step‐ahead forecast in achieving higher trading profits. Copyright © 2000 John Wiley & Sons, Ltd.     

Cimetidine induces hepatic heme oxygenase activity without altering hepatic heme catabolism

Cimetidine inhibits oxidative drug metabolism; it is not known whether this drug alters the catabolic fate of hepatic heme. We therefore investigated hepatic heme turnover both by a 14CO breath test and directly by labeling the heme pool. Neither acute (150 mg/kg i.p.) nor chronic (150 mg/kg i.p. bid for 3 days) cimetidine administration significantly affected hepatic heme turnover. Chronic, but not acute, cimetidine significantly (p less than 0.025) increased heme oxygenase activity. Cimetidine inhibited heme oxygenase activity in vitro at concentrations achieved in vivo.     

Cys-tRNACys formation and cysteine biosynthesis in methanogenic archaea: two faces of the same problem?

Aminoacyl-tRNA (transfer RNA) synthetases are essential components of the cellular translation machinery as they provide the ribosome with aminoacyl-tRNAs. Aminoacyl-tRNA synthesis is generally well understood. However, the mechanism of Cys-tRNACys formation in three methanogenic archaea ( Methanocaldococcus jannaschii, Methanothermobacter thermautotrophicus and Methanopyrus kandleri) is still unknown, since no recognizable gene for a canonical cysteinyl-tRNA synthetase could be identified in the genome sequences of these organisms. Here we review the different routes recently proposed for Cys-tRNACys formation and discuss its possible link with cysteine biosynthesis in these methanogenic archaea.     

Etamsylate as inhibitor of prostaglandin biosynthesis in pregnant human myometrium in vitro

Summary The effects of etamsylate on prostaglandin (PG) biosynthesis in microsomes of pregnant human myometrium in vitro have been determined, and compared with those of indomethacin. Both drugs inhibited PG biosynthesis, indomethacin being the more potent inhibitor of the two. Etamsylate inhibited synthesis of 6-oxo-PGF₁, PGF₂, PGE₂, and thromboxane B₂; increasing the concentration of etamsylate increased the inhibition of synthesis. It is suggested that etamsylate has no anti-cyclo-oxygenase activity, but acts by inhibiting the activity of prostacyclin synthetase, endoperoxide reductase, endoperoxide isomerase, and thromboxane synthetase.     

Sensitivity of univariate AR(1) time‐series forecasts near the unit root

We consider the linear time‐series model y_t=d_t+u_t(t=1,...,n), where d_t is the deterministic trend and u_t the stochastic term which follows an AR(1) process; u_t=θu_t−1+ϵ_t, with normal innovations ϵ_t. Various assumptions about the start‐up will be made. Our main interest lies in the behaviour of the l‐period‐ahead forecast y_n+1 near θ=1. Unlike in other studies of the AR(1) unit root process, we do not wish to ask the question whether θ=1 but are concerned with the behaviour of the forecast estimate near and at θ=1. For this purpose we define the sth (s=1,2) order sensitivity measure λ_l^(s) of the forecast y_n+1 near θ=1. This measures the sensitivity of the forecast at the unit root. In this study we consider two deterministic trends: d_t=β_t and d_t=β_t+β_tt. The forecast will be the Best Linear Unbiased forecast. We show that, when d_t=β_t, the number of observations has no effect on forecast sensitivity. When the deterministic trend is linear, the sensitivity is zero. We also develop a large‐sample procedure to measure the forecast sensitivity when we are uncertain whether to include the linear trend. Our analysis suggests that, depending on the initial conditions, it is better to include a linear trend for reduced sensitivity of the medium‐term forecast. Copyright © 2001 John Wiley & Sons, Ltd.     

Steroidal sapogenins. XXX stereochemistry of the side chain

Zusammenfassung Die optischen Drehungen einiger 20, 25d; 20, 25l; 20, 25d; und 20, 25-l-Sapogenine wurden bestimmt. Die ersten drei Serien gaben übereinstimmend linksdrehende Werte, aber die letztere Gruppe erwies sich als rechtsdrehend.Die Struktur der vier Serien der Sapogenine folgte aus der Analyse dieser Befunde. Der mögliche Mechanismus bei der Entstehung dieser Verbindungen aus Pseudosapogeninen wurde besprochen. Die Autoren gelangen zum Schluss, dass sterische Faktoren an C₂₀ und C₂₅ die Richtung der Ringschliessung beeinflussen.

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Steroidal sapogenins. XXX stereochemistry of the side chain