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PubMed1983

Effects of estrogen and testosterone on the metabolism of mevalonate by the shunt pathway.

Mevalonate is metabolized by a sterol-forming and a non-sterol-forming, also called the "shunt", pathway. Effects of estrogen and testosterone administration on the shunt activity were examined in male and female Wistar and Sprague-Dawley rats. Shunt activity was determined in vivo from the yield of expired 14CO2 following [5-14C]mevalonate injection. Total mevalonate utilized was determined from the yield of expired 14CO2 following [1-14C]mevalonate injection. In the female, about 45% of mevalonate appears to be metabolized via the shunt, and in the male about 20%. This difference between male and female rats is dependent on both testosterone and estrogen, and apparently on testosterone to a greater extent. Thus estrogen treatment produced a 20-35% increase in shunt activity over castrated controls, while castration of males without hormonal treatment resulted in about a 50% increase in shunt activity, and testosterone administration returned castrated male and female shunt activity to that of intact males, or nearly so. Light/dark cycle had no effect in vivo on shunt activity, but may be critical in demonstrating sex differences in shunt activity in kidney slices.

Animals↗
PubMed2003

Pitavastatin inhibits vascular smooth muscle cell proliferation by inactivating extracellular signal-regulated kinases 1/2.

We recently reported that lysophosphatidylcholine (lysoPC) acts on vascular smooth muscle cells ( VSMCs ) to produce a mitogenic response through the activation of extracellular signal-regulated kinases 1/2 (ERK1/2). In this study, we examined the role of HMG-CoA reductase inhibitors on lysoPC-induced VSMC proliferation. Pitavastatin, a new HMG-CoA reductase inhibitor, suppressed lysoPC-induced DNA synthesis in primary cultured rat VSMCs. Since lysoPC-induced ERK1/2 activation contributes to smooth muscle cell proliferation, we explored the effect of pitavastatin on ERK1/2 activation. Pitavastatin inhibited lysoPC-induced ERK1/2 phosphorylation and ERK1/2 activation. The other HMG-CoA reductase inhibitors, atrovastatin and fluvastatin, also inhibited lysoPC-induced ERK1/2 phosphorylation. Pitavastatin also inhibited lysoPC-induced c-fos mRNA expression. To gain insight into the mechanism of the inhibitory effect of pitavastatin on ERK1/2 activation by lysoPC, we examined the role of the mevalonate pathways. Mevalonate and farnesylpyrophosphate reduced the inhibition of ERK1/2 phosphorylation by pitavastatin. These studies demonstrate that pitavastatin may inhibit lysoPC-induced VSMC proliferation, at least in part, by inactivating ERK1/2, which is linked to mevalonate metabolism.

Animals↗
PubMed2005

Independent pathways in the modulation of osteoclastic resorption by intermediates of the mevalonate biosynthetic pathway: the role of the retinoic acid receptor.

Geranylgeranyl pyrophosphate (GGPP) and geranylgeraniol (GGOH) are used for the prenylation of GTP binding proteins and can reverse the antiresorptive action of nitrogen-containing bisphosphonates which inhibit farnesyl pyrophosphate synthase, an enzyme of the mevalonate pathway involved in the formation of GGPP. Previously, in cultures of fetal mouse long bones, we showed that GGOH stimulates osteoclastic bone resorption, but the cellular and molecular mode of action is not known. In cell homogenates, it has been found that GGOH can be metabolized to geranylgeranoic acid (GGA) which, like retinoic acid (RA), is a stimulator of retinoic acid receptor (RAR) expression. For this, we examined the involvement of the RAR in the action of GGOH on bone resorption. We show here that RA, GGOH, GGPP and GGA stimulate osteoclastic bone resorption and that this action is reversed by the RAR antagonist AGN-193109. These findings indicate the functional involvement of the RAR in the action of these polyisoprenoids. Moreover, RA, GGOH and GGA all stimulated RARbeta mRNA expression in bone explants. However, in contrast to GGOH and GGPP, GGA was not able to reverse the antiresorptive action of ibandronate, a nitrogen-containing bisphosphonate, suggesting that GGA is not involved in protein prenylation. In conclusion, our studies show that both GGOH and GGPP, independent of protein prenylation, stimulate osteoclastic bone resorption via RAR, probably via metabolism into GGA. Identification of such mechanism can help in the better understanding of the role of this metabolic pathway in the regulation of the activity and survival of osteoclasts.

Animals↗
PubMed1999

Isopentenyl diphosphate biosynthesis via a mevalonate-independent pathway: isopentenyl monophosphate kinase catalyzes the terminal enzymatic step.

In plants, the biosynthesis of isopentenyl diphosphate, the central precursor of all isoprenoids, proceeds via two separate pathways. The cytosolic compartment harbors the mevalonate pathway, whereas the newly discovered deoxyxylulose 5-phosphate pathway, which also operates in certain eubacteria, including Escherichia coli, is localized to plastids. Only the first two steps of the plastidial pathway, which involve the condensation of pyruvate and glyceraldehyde 3-phosphate to deoxyxylulose 5-phosphate followed by intramolecular rearrangement and reduction to 2-C-methylerythritol 4-phosphate, have been established. Here we report the cloning from peppermint (Mentha x piperita) and E. coli, and expression, of a kinase that catalyzes the phosphorylation of isopentenyl monophosphate as the last step of this biosynthetic sequence to isopentenyl diphosphate. The plant gene defines an ORF of 1,218 bp that, when the proposed plastidial targeting sequence is excluded, corresponds to approximately 308 aa with a mature size of approximately 33 kDa. The E. coli gene (ychB), which is located at 27.2 min of the chromosomal map, consists of 852 nt, encoding a deduced enzyme of 283 aa with a size of 31 kDa. These enzymes represent a conserved class of the GHMP family of kinases, which includes galactokinase, homoserine kinase, mevalonate kinase, and phosphomevalonate kinase, with homologues in plants and several eubacteria. Besides the preferred substrate isopentenyl monophosphate, the recombinant peppermint and E. coli kinases also phosphorylate isopentenol, and, much less efficiently, dimethylallyl alcohol, but dimethylallyl monophosphate does not serve as a substrate. Incubation of secretory cells isolated from peppermint glandular trichomes with isopentenyl monophosphate resulted in the rapid production of monoterpenes and sesquiterpenes, confirming that isopentenyl monophosphate is the physiologically relevant, terminal intermediate of the deoxyxylulose 5-phosphate pathway.

Amino Acid Sequence↗
PubMed1987

Contribution of the shunt pathway of mevalonate metabolism to the regulation of cholesterol synthesis in rat liver.

The modulation of the shunt pathway of mevalonate metabolism (Edmond, J., and Popják, G. (1974) J. Biol. Chem. 249, 66-71) has been studied in livers from fed, starved, and diabetic rats perfused with a physiological concentration (300 nM) of [5-14C] + [5-3H]mevalonate. Shunt activity was measured by (i) production of 14CO2 (corrected for loss of label by exchange reactions) and (ii) production of 3H2O. Contribution of exogenous mevalonate to total mevalonate production (0.06-0.11%) was assessed in parallel experiments by the incorporation of 3H2O into sterols. Inhibition of non-saponifiable lipid synthesis by starvation and diabetes is not associated with an inhibition of mevalonate production but with a major increase in shunting (7-34%) of sterol-bound mevalonate. The shunt pathway of mevalonate metabolism appears to participate in the regulation of cholesterol synthesis.

Animals↗
PubMed2004

HMG-CoA reductase inhibition causes neurite loss by interfering with geranylgeranylpyrophosphate synthesis.

To determine whether neurite outgrowth depends upon the mevalonate pathway, we blocked mevalonate synthesis in nerve growth factor-treated PC12 cells or primary cortical neurones with atorvastatin, a 3-hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and substituted different intermediates of the mevalonate pathway. We show that HMG-CoA reductase inhibition causes a profound reduction of neurite length, neurite loss and ultimatively cell death in undifferentiated and pre-differentiated PC12 cells and also in rat primary cortical neurones. Geranylgeranylpyrophosphate, but not farnesylpyrophosphate, squalene or cholesterol, completely compensated for the lack of mevalonate. Our data indicate that, under HMG-CoA reductase inhibition, geranylgeranylpyrophosphate rather than farnesylpyrophosphate or cholesterol is critical for neurite outgrowth and/or maintenance. Loss of neurites is an early manifestation of various neurodegenerative disorders, and dysfunction of isoprenylation might play a role in their pathogenesis.

Animals↗
PubMed2003

Effects of brassinazole, an inhibitor of brassinosteroid biosynthesis, on light- and dark-grown Chlorella vulgaris.

Treatment of cultured Chlorella vulgaris Beijerinck cells with 0.1-10 microM brassinazole (Brz2001), an inhibitor of brassinosteroid (BR) biosynthesis, inhibits their growth during the first 48 h of cultivation in the light. This inhibition is prevented by the co-application of BR. This result suggests that the presence of endogenous BRs during the initial steps of the C. vulgaris cell cycle is indispensable for their normal growth in the light. In darkness, a treatment with 10 nM brassinolide (BL) promotes growth through the first 24 h of culture, but during the following 24 h the cells undergo complete stagnation. Treatment of dark-grown cells with either Brz2001 alone, or a mixture of 10 nM BL and 0.1/10 microM Brz2001, also stimulates their growth. The effects of treatment with 10 nM BL mixed with 0.1-10 microM of a mevalonate-pathway inhibitor (mevinolin), or a non-mevalonate-pathway inhibitor (clomazone), were also investigated. Mevinolin at these concentrations did not inhibit growth of C. vulgaris; however, clomazone did. Addition of BL overcame the inhibition. These results suggest that the mevalonate pathway does not function in C. vulgaris, and that the non-mevalonate pathway for isopentenyl diphosphate biosynthesis is responsible for the synthesis of one of the primary precursors in BR biosynthesis.

Brassinosteroids↗
PubMed1984

The shunt pathway of mevalonate metabolism in the isolated perfused rat kidney.

The shunt pathway of mevalonate metabolism (Edmond, J., and Popják, G. (1974) J. Biol. Chem. 249, 66-71) has been studied in isolated kidneys from rats perfused with physiological concentrations of variously labeled [14C]- and [3H]mevalonates. The rate of operation of the shunt pathway was quantified by the production of either 14CO2 or 3H2O from the tracers. The measured rates of 14CO2 production from [14C] mevalonate were converted to rates of mitochondrial acetyl-CoA production by methods which take into account underestimations of metabolic rates derived from 14CO2 production. We have shown that the sex difference in renal shunting of mevalonate (Wiley, M. H., Howton, M. M., and Siperstein, M. D. (1979) J. Biol. Chem. 254, 837-842) occurs at physiological levels of substrate. The shunt pathway diverts up to 17% of the flux of mevalonate entering the cholesterol synthesis pathway in the kidney. It may, therefore, play a role in the long term regulation of cholesterol synthesis in this organ, as had been hypothesized by Edmond and Popják.

Acetyl Coenzyme A↗
PubMed1982

Evidence for an underestimation of the shunt pathway of mevalonate metabolism in slices of livers and kidneys from fasted rats and rats in diabetic ketosis.

Yields of (14)CO(2) from [2-(14)C]mevalonate and [5-(14)C]mevalonate have been used by others to estimate the activity of the non-sterol-forming pathway, also called the mevalonate shunt pathway, and yields of (14)C in sterols have been used to estimate the activity of the sterol-forming pathway. Both these pathways operate following the conversion of carbon 1 of mevalonate to CO(2). The estimations of the shunt pathway contribution are dependent upon the fractions of carbons 2 and 5 of mevalonate that are oxidized to CO(2) in the Krebs cycle after leaving the pathway. Unless all of carbons 2 and 5 are oxidized to CO(2), the estimates are minimal. The metabolism of mevalonate has now been examined in slices of livers and kidneys from fasted rats and rats in diabetic ketosis. Yields of (14)CO(2) from [1-(14)C]mevalonate are used as the measure of the contributions of all the pathways by which carbon 1 of mevalonate is converted to CO(2). Yields of (3)H-labeled nonsaponifiable lipids from [5-(3)H]mevalonate are used as the measure of the sterol-forming pathway. The differences in these yields are then taken as the measure of the non-sterol-forming pathway or pathways. Yields of (14)CO(2) from [1-(14)C]mevalonate markedly exceeded the sum of the yields of (14)C in CO(2) and nonsaponifiable lipids from either [2-(14)C]mevalonate or [5-(14)C]mevalonate. Therefore, in liver and kidney, under the conditions of this study, either one or more pathways other than the shunt pathway, by which mevalonate can be metabolized to other than sterols, is operative to a marked degree, or estimates of the shunt pathway's contributions as judged by yields of (14)CO(2) from [2-(14)C]mevalonate and [5-(14)C]mevalonate are significantly underestimated.-Brady, P. S., W. C. Schumann, S. Ohgaku, R. F. Scofield, and B. R. Landau. Evidence for an underestimation of the shunt pathway of mevalonate metabolism in slices of livers and kidneys from fasted rats and rats in diabetic ketosis.

Animals↗
PubMed2002

Distinct mechanisms of bisphosphonate action between osteoblasts and breast cancer cells: identity of a potent new bisphosphonate analogue.

While the effects of bisphosphonates on bone-resorbing osteoclasts have been well documented, the effects of bisphosphonates on other cell types are not as well studied. Recently, we reported that bisphosphonates have direct effects on bone-forming human fetal osteoblast cells (hFOB). In this report, the role of the mevalonate pathway in the actions of bisphosphonates on hFOB, and MDA-MB-231 human breast cancer cells was examined. These studies included a novel bisphosphonate analog, the anhydride formed between arabinocytidine 5' phosphate and etidronate (Ara-CBP). Ara-CBP was the most potent inhibitor of hFOB and MDA-MB-231 cell proliferation, and stimulator of hFOB cell mineralization compared to etidronate, the anhydride formed between AMP and etidronate (ABP), pamidronate, and zoledronate. Inhibition of hFOB cell proliferation by Ara-CBP and zoledronate was partially reversed by mevalonate pathway intermediates, and stimulation of hFOB cell mineralization was completely reversed by mevalonate pathway intermediates. These results suggest that zoledronate and Ara-CBP act, at least in part, via inhibition of the mevalonate pathway in hFOB cells. In contrast, none of the mevalonate pathway intermediates reversed the inhibition of MDA-MB-231 cell proliferation by the bisphosphonates, or the effects of pamidronate on hFOB cells. As a positive control, the effects of mevastatin on hFOB and MDA-MB-231 cells were completely reversed by mevalonate. In summary, these data suggest that zoledronate and Ara-CBP induce human osteoblast differentiation via inhibition of the mevalonate pathway. In contrast, the inhibition of MDA-MB-231 cell proliferation by the bisphosphonates appears to be through mechanisms other than inhibition of the mevalonate pathway.

Bone and Bones↗
PubMed1993

Procedures for the isolation and quantification of the intermediates of the mevalonic acid pathway.

Procedures for the isolation and analysis of all 11 intermediates of the mevalonic acid pathway from acetyl-CoA through geranylgeranyl pyrophosphate were developed. Both acid-labile and base-labile metabolites are simultaneously extracted with good recoveries into 7 M urea at neutral pH and low temperature to minimize hydrolytic and degradative enzyme losses, and the extract is partially purified by adsorption and desorption in high yield from an anion-exchange membrane. With the use of internal standards, the pathway intermediates are subsequently separated and quantified by reversed-phase ion-pair HPLC with on-line radiodetection. Permeable secretory cells specialized for monoterpene biosynthesis were isolated from peppermint (Mentha x piperita) leaves and employed as a model system to test the analytical protocols by examining the incorporation of [14C]pyruvate, [14C]mevalonate, and [3H]isopentenyl pyrophosphate as precursors. This simple new method should be readily adaptable to a wide range of cell and tissue types that can be administered basic metabolic precursors, and should allow measurements of both flux and steady-state levels of the intermediates of the mevalonic acid pathway.

Acetyl Coenzyme A↗
PubMed1984

The shunt pathway of mevalonate metabolism in the isolated perfused rat liver.

The shunt pathway of mevalonate metabolism (Edmond, J., and Popják, G. (1974) J. Biol. Chem. 249, 66-71) has been studied in isolated livers from fed rats perfused with physiological concentrations of variously labeled [14C]mevalonates. The measured rates of 14CO2 production were converted to rates of mitochondrial acetyl-CoA production from mevalonate by methods which take into account underestimations of metabolic rates derived from 14CO2 production. Our data confirm that the shunt pathway leads to mitochondrial acetyl-CoA. The apparent negligible rate of mevalonate shunting in liver, previously reported by others, stems from the very low contribution (congruent to 0.1%) of plasma mevalonate to total mevalonate metabolism in the liver. This contribution was assessed from the relative incorporations of 3H2O and [5-14C]mevalonate into sterols. In livers from fed rats, the shunt diverts about 5% of the production of mevalonate. The total rate of mevalonate shunting in the liver is about 200 times greater than in two kidneys. The liver is therefore the main site of mevalonate shunting in the rat.

Acetyl Coenzyme A↗
PubMed1997

Biosynthesis of isoprenoids in higher plant chloroplasts proceeds via a mevalonate-independent pathway.

Isopentenyl diphosphate (IPP) is the biological C5 precursor of isoprenoids. By labeling experiments using [1-(13)C]glucose, higher plants were shown to possess two distinct biosynthetic routes for IPP biosynthesis: while the cytoplasmic sterols were formed via the acetate/mevalonate pathway, the chloroplast-bound isoprenoids (beta-carotene, lutein, prenyl chains of chlorophylls and plastoquinone-9) were synthesized via a novel IPP biosynthesis pathway (glyceraldehyde phosphate/pyruvate pathway) which was first found in eubacteria and a green alga. The dichotomy in isoprenoid biosynthesis in higher plants allows a reasonable interpretation of previous odd and inconclusive results concerning the biosynthesis of chloroplast isoprenoids, which so far had mainly been interpreted in the frame of models using compartmentation of the mevalonate pathway.

Chloroplasts↗
PubMed2004

Production of mevalonate by a metabolically-engineered Escherichia coli.

Mevalonate is biosynthesized from acetyl-CoA and metabolized to isoprenoid compounds in a wide variety of organisms although certain types of prokaryotes employ another route for isoprenoid biosynthesis (the non-mevalonate pathway). To establish a fermentative process for mevalonate production, enzymes for mevalonate synthesis from Enterococcus faecalis were expressed in Escherichia coli, a non-mevalonate pathway bacterium. Mevalonate was accumulated, indicating a redirection of acetate metabolism by the expressed enzyme. The recombinant E. coli produced 47 g mevalonate l(-1) in 50 h of fed-batch cultivation in a 2 l jar fermenter; this is the highest titer ever reported demonstrating the superiority of E. coli in its ability of acetyl-CoA supply and its inability is degrade mevalonate.

Acetates↗
PubMed2004

[Cloning and analysis of cDNA encoding key enzyme gene (dxr) of the non-MVA pathway in Taxus chinensis cells].

Two distinct routes (classical mevalonate pathway and a novel mevalonate-independent pathway) are utilized by plants for the biosynthesis of isopentenyl diphosphate, the universal precursor of isoprenoids (Fig. 1). Present researches indicated that taxol was synthesized mainly via non-mevalonate pathway, but not genetic evidence was showed. The second step in non-mevalonate pathway involves an intramolecular rearrangement and subsequent reduction of deoxyxylulose phosphate to yield 2-C-methyl-D-erythritol-4-phosphate, and 1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) with responsibility for this reaction was considered as a key enzyme. As a tool for the isolation of genes in terpenoid biosynthesis in plants, total RNA was prepared from Taxus chinensis suspension cells, a cell type highly specialized for diterpene (taxol). A reverse transcription-PCR strategy based on the design of degenerated oligonucleotides was developed for isolating the gene encoding a gymnosperm homolog of this enzyme from Taxus chinensis. Through sequence analysis by Blast P online, the resulting cDNA showed highly homologous to 1-deoxy-D-xylulose 5-phosphate reductoisomerases, with 95% identification compared with Arabidopsis thaliana (Q9XFS9), 94% with Mentha x piperita (Q9XESO), 80% with Synechococcus elongatus (Q8DK30), 78% with Synechocystis sp. PCC 6803 (Q55663) and Nostoc sp. PCC 7120 (Q8YP49), and 73% with Synechococcus leopoliensis (Q9RKT1). Deduced amino acid sequences were also analyzed by PROSITE, ClustalX (1.81) and Phylio (3.6 alpha), and data present evidence for the existence of this deoxyxyluose phosphate reductoisomerase in Taxus chinensis. This is the first report of the dxr gene cloned from gymnosperm.

Aldose-Ketose Isomerases↗
PubMed2006

Brain cholesterol turnover required for geranylgeraniol production and learning in mice.

The mevalonate pathway produces cholesterol and nonsterol isoprenoids, such as geranylgeraniol. In the brain, a fraction of cholesterol is metabolized in neurons by the enzyme cholesterol 24-hydroxylase, and this depletion activates the mevalonate pathway. Brains from mice lacking 24-hydroxylase excrete cholesterol more slowly, and the tissue compensates by suppressing the mevalonate pathway. Here we report that this suppression causes a defect in learning. 24-Hydroxylase knockout mice exhibit severe deficiencies in spatial, associative, and motor learning, and in hippocampal long-term potentiation (LTP). Acute treatment of wild-type hippocampal slices with an inhibitor of the mevalonate pathway (a statin) also impairs LTP. The effects of statin treatment and genetic elimination of 24-hydroxylase on LTP are reversed by a 20-min treatment with geranylgeraniol but not by cholesterol. We conclude that cholesterol turnover in brain activates the mevalonate pathway and that a constant production of geranylgeraniol in a small subset of neurons is required for LTP and learning.

Animals↗
PubMed2001

Peroxisome proliferators and fatty acids negatively regulate liver X receptor-mediated activity and sterol biosynthesis.

Peroxisome proliferators (PPs) are potent tumor promoters in rodents. The mechanism of hepatocarcinogenesis requires the nuclear receptor peroxisome proliferator activated receptor-alpha (PPARalpha), but might also involve the PPARalpha independent alteration of signaling pathways that regulate cell growth. Here, we studied the effects of PPs on the mevalonate pathway, a critical pathway that controls cell proliferation. Liver X receptors (LXRs) are nuclear receptors that act as sterol sensors in the mevalonate pathway. In gene reporter assays in COS-7 cells, the basal activity of the LXR responsive reporter gene (LXRE-luc) was suppressed by 10 microM lovastatin and zaragozic acid A, suggesting that this activity was attributed to the activation of native LXRs, by endogenously produced mevalonate products. The potent PP and rodent tumor promoter, pirinixic acid (WY-14643) also inhibited LXR-mediated transcription in a dose related manner (approximate IC(50) of 100 microM). As did several other PPs including ciprofibric acid and mono-ethylhexylphthalate. Polyunsaturated and medium to long chain fatty acids at 100 microM were also potent inhibitors; the arachidonic acid analogue eicosatetraynoic acid being the most active (approximate IC(50) of 10 microM). Of the PPs and fatty acids tested, there was a strong correlation between the ability of these agents to suppress de novo sterol synthesis in a rat hepatoma cell line, H4IIEC3, and inhibit LXR-mediated transcription in COS-7 cells, but a discordance between these endpoints and PPARalpha activation and fatty acid acyl-CoA oxidase induction. Taken together, these results suggest that PPs and fatty acids negatively regulate the mevalonate pathway through a mechanism that is not entirely dependent on PPARalpha activation. Because of the importance of the mevalonate pathway in regulating cell proliferation, the modulation of this pathway by PPs and fatty acids might contribute to their actions on cell growth/differentiation.

Acyl-CoA Oxidase↗
PubMed2002

Structure of 2C-methyl-d-erythritol-2,4-cyclodiphosphate synthase involved in mevalonate-independent biosynthesis of isoprenoids.

Isoprenoids are biosynthesized from isopentenyl diphosphate and the isomeric dimethylallyl diphosphate via the mevalonate pathway or a mevalonate-independent pathway that was identified during the last decade. The non-mevalonate pathway is present in many bacteria, some algae and in certain protozoa such as the malaria parasite Plasmodium falciparum and in the plastids of higher plants, but not in mammals and archaea. Therefore, these enzymes have been recognised as promising drug targets. We report the crystal structure of Escherichia coli 2C- methyl-d-erythritol-2,4-cyclodiphosphate synthase (IspF), which converts 4-diphosphocytidyl-2C-methyl-d-erythritol 2-phosphate into 2C-methyl-d-erythritol 2,4-cyclodiphosphate and CMP in a Mg-dependent reaction. The protein forms homotrimers that tightly bind one zinc ion per subunit at the active site, which helps to position the substrate for direct attack of the 2-phosphate group on the beta-phosphate.

Amino Acid Motifs↗