Animal disease models generated by genetic engineering of polyamine metabolism

Jänne, Juhani; Alhonen, Leena; Keinänen, Tuomo A.; Pietilä, Marko; Uimari, Anne; Pirinen, Eija; Hyvönen, Mervi T.; Järvinen, Aki

doi:10.1111/j.1582-4934.2005.tb00385.x

Cited by 54 publications

(36 citation statements)

References 88 publications

(130 reference statements)

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“…In humans, the concentration in CSF of spermine is greater than that of other polyamines, such as putrescine and spermidine, 36) although the whole blood concentration of spermine is similar to that of spermidine. 37) Since spermine is the end-product of polyamine bio-synthesis, [6][7][8] it is considered that this carrier-mediated spermine efflux transport at the BCSFB takes part in the modulation of polyamine concentrations in the brain. Therefore, this finding will help in our understanding of neural concentration homeostasis of polyamines, including spermine, and thus modulation of neuro-exciting signal transduction via spermine-related Nmethyl-D-aspartate pathways.…”

Section: Resultsmentioning

confidence: 99%

“…The precursor of spermine is spermidine, 5) which is synthesized from putrescine and it has been reported that the biosynthesis of spermine from spermidine is superior to that of spermidine from spermine. [6][7][8] Hence, neural spermine transport system(s) could be important for the removal of spermine from the brain, and the modulation of cerebral spermine concentration.…”

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confidence: 99%

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Involvement of Carrier-Mediated Transport at the Blood–Cerebrospinal Fluid Barrier in Spermine Clearance from Rat Brain

Akanuma

Shimada

Kubo

et al. 2017

Biological & Pharmaceutical Bulletin

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Spermine is the end-product in the polyamine biosynthetic pathway, and its excess accumulation induces neuroexcitatory responses and neurotoxicity. The purpose of this study was to elucidate the involvement of transport systems at the brain barriers in the clearance of spermine. In vivo rat spermine elimination from brain parenchyma across the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier (BCSFB) was assessed by intracerebral and intracerebroventricular administration techniques, respectively. To characterize spermine transport at the BCSFB, a transport study using rat choroid plexus was performed. After the intracerebral microinjection of [ Spermine is a natural polyamine, and the end-product in the polyamine biosynthetic pathway.1) In the brain, spermine binds to N-methyl-D-aspartate receptors, and is involved in the modulation of learning and memory.2,3) In addition, excess accumulation of spermine induces neuroexcitatory responses and, thus, neurotoxicity. 4) Therefore, it is considered that some mechanisms for control of the cerebral spermine concentration are present in the brain to maintain homeostasis of cerebral function via spermine-related neuro-responses. The precursor of spermine is spermidine, 5) which is synthesized from putrescine and it has been reported that the biosynthesis of spermine from spermidine is superior to that of spermidine from spermine.6-8) Hence, neural spermine transport system(s) could be important for the removal of spermine from the brain, and the modulation of cerebral spermine concentration.Brain parenchyma and cerebrospinal fluid (CSF) are separated from the circulating blood by the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), respectively. The BBB and BCSFB are formed by brain capillary endothelial and choroid plexus epithelial cells, respectively, and express some transporting molecules which are involved in active elimination of compound from the brain or CSF.9) Regarding the cationic compound elimination system(s) at these barriers, mRNAs of plasma membrane monoamine transporter (PMAT/ solute carrier (SLC)29A4), organic cation/carnitine transporter 1-2 (OCTN1-2/SLC22A4-5), organic cation transporter 1-3 (OCT1-3/SLC22A1-3), and multidrug and toxin extrusion 1-2 (MATE1-2/SLC47A1-2) are expressed in rat BBB and BCSFB cell lines. 10) Among these transporters, PMAT is, at least in part, involved in brain/CSF-to-blood transport of 1-methyl-4-phenylpyridinium (MPP + ) 10) and CSF-to-blood transport of histamine.11) In addition, OCT3 takes part in the efflux transport of creatinine, a cationic guanidino compound.12) Therefore, it is possible that cerebral spermine is eliminated across these brain barriers.Some previous studies have reported that polyamines including spermine are transported in a carrier-mediated manner in some organs and it has been reported that carrier-mediated transport of polyamines is present in mammalian intestine, liver, and kidney. [13][14][15] In addition, we have demonstrated that the rat inner blood-retinal barr...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Involvement of Carrier-Mediated Transport at the Blood–Cerebrospinal Fluid Barrier in Spermine Clearance from Rat Brain

Akanuma

Shimada

Kubo

et al. 2017

Biological & Pharmaceutical Bulletin

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“…Polyamines are strongly associated with cell proliferation, up-regulated in many cancers, and essential for liver regeneration, so circadian regulation of this pathway may gate the hepatocyte's permissibility to initiate liver regeneration (27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Cell-autonomous circadian clock of hepatocytes drives rhythms in transcription and polyamine synthesis

Atwood

DeConde²,

Wang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The circadian clock generates daily rhythms in mammalian liver processes, such as glucose and lipid homeostasis, xenobiotic metabolism, and regeneration. The mechanisms governing these rhythms are not well understood, particularly the distinct contributions of the cell-autonomous clock and central pacemaker to rhythmic liver physiology. Through microarray expression profiling in Met murine hepatocytes (MMH)-D3, we identified over 1,000 transcripts that exhibit circadian oscillations, demonstrating that the cell-autonomous clock can drive many rhythms, and that MMH-D3 is a valid circadian model system. The genes represented by these circadian transcripts displayed both cophasic and antiphasic organization within a protein-protein interaction network, suggesting the existence of competition for binding sites or partners by genes of disparate transcriptional phases. Multiple pathways displayed enrichment in MMH-D3 circadian transcripts, including the polyamine synthesis module of the glutathione metabolic pathway. The polyamine synthesis module, which is highly associated with cell proliferation and whose products are required for initiation of liver regeneration, includes enzymes whose transcripts exhibit circadian oscillations, such as ornithine decarboxylase and spermidine synthase. Metabolic profiling revealed that the enzymatic product of spermidine synthase, spermidine, cycles as well. Thus, the cell-autonomous hepatocyte clock can drive a significant amount of transcriptional rhythms and orchestrate physiologically relevant modules such as polyamine synthesis.networks | chronobiology | resistance distance M any aspects of mammalian physiology and behavior display circadian (∼24-h) rhythms, including the sleep/wake cycle, blood pressure, heart rate, metabolism, and liver regeneration (1, 2). These rhythms are regulated by the circadian clock, which enables consolidation and coordination of physiological events to specific phases of the 24-h cycle in anticipation of daily environmental changes. Dysfunction of the clock is associated with serious human health conditions, including shift work syndrome, sleep disorders, increased risk of cancer, cardiovascular disease, and metabolic syndrome (1, 2).The circadian clock is a self-sustaining, entrainable, cell-autonomous network of three interlocked transcriptional negative feedback loops (2). The primary loop consists of BMAL1/CLOCK transcriptional activators, which dimerize and turn on transcription of Period (Per1, Per2, and Per3) and Crytochrome (Cry1 and Cry2) genes through E-box elements. PER and CRY proteins dimerize and feed back to inhibit BMAL1/CLOCK activation. Two associate loops interlock with the core loop: the ROR/REV-ERB element (RRE) loop composed of ROR activators (RORa, RORb, and RORc) and REV-ERB repressors (REV-ERBα and REV-ERBβ), which compete for RRE transcription factor binding sites (TFBS), and the D-box loop composed of the activator DBP and repressor E4BP4, which act through D-box TFBS (2).In addition to internal regulation of clock genes,...

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“…Putrescine [4], spermidine [34], and spermine [343] are polyamines commonly observed in the cells of various living organisms, from viruses to humans (1)(2)(3)(4). Polyamines are important in cell proliferation and cell differentiation (5,6), as well as contributing to adaptation to various stresses (7). Interestingly, in addition to common polyamines, thermophiles contain two types of unusual polyamines as major polyamines.…”

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confidence: 99%

Identification of a Novel Aminopropyltransferase Involved in the Synthesis of Branched-Chain Polyamines in Hyperthermophiles

et al. 2014

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f Longer-and/or branched-chain polyamines are unique polycations found in thermophiles. N 4 -aminopropylspermine is considered a major polyamine in Thermococcus kodakarensis. To determine whether a quaternary branched penta-amine, N 4 -bis(aminopropyl)spermidine, an isomer of N 4 -aminopropylspermine, was also present, acid-extracted cytoplasmic polyamines were analyzed by high-pressure liquid chromatography, gas chromatography (HPLC), and gas chromatography-mass spectrometry. N 4 -bis(aminopropyl)spermidine was an abundant cytoplasmic polyamine in this species. To identify the enzyme that catalyzes N 4 -bis(aminopropyl)spermidine synthesis, the active fraction was concentrated from the cytoplasm and analyzed by linear ion trap-time of flight mass spectrometry with an electrospray ionization instrument after analysis by the MASCOT database. TK0545, TK0548, TK0967, and TK1691 were identified as candidate enzymes, and the corresponding genes were individually cloned and expressed in Escherichia coli. Recombinant forms were purified, and their N 4 -bis(aminopropyl)spermidine synthesis activity was measured. Of the four candidates, TK1691 (BpsA) was found to synthesize N 4 -bis(aminopropyl)spermidine from spermidine via N 4 -aminopropylspermidine. Compared to the wild type, the bpsA-disrupted strain DBP1 grew at 85°C with a slightly longer lag phase but was unable to grow at 93°C. HPLC analysis showed that both N 4 -aminopropylspermidine and N 4 -bis(aminopropyl)spermidine were absent from the DBP1 strain grown at 85°C, demonstrating that the branched-chain polyamine synthesized by BpsA is important for cell growth at 93°C. Sequence comparison to orthologs from various microorganisms indicated that BpsA differed from other known aminopropyltransferases that produce spermidine and spermine. BpsA orthologs were found only in thermophiles, both in archaea and bacteria, but were absent from mesophiles. These findings indicate that BpsA is a novel aminopropyltransferase essential for the synthesis of branched-chain polyamines, enabling thermophiles to grow in high-temperature environments. P olyamines are small, positively charged aliphatic molecules containing more than two amine residues present in almost all living organisms. Putrescine [4], spermidine [34], and spermine [343] are polyamines commonly observed in the cells of various living organisms, from viruses to humans (1-4). Polyamines are important in cell proliferation and cell differentiation (5, 6), as well as contributing to adaptation to various stresses (7). Interestingly, in addition to common polyamines, thermophiles contain two types of unusual polyamines as major polyamines. One type consists of long linear polyamines such as caldopentamine [3333] NH, N,. Because the relative amounts of long/branched-chain polyamines in cells of (hyper)thermophiles were found to increase as growth temperatures increased, these unique polyamines are regarded as supporting the growth of thermophilic microorganisms under high-temperature conditions (18)(19)(20). An in...

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Animal disease models generated by genetic engineering of polyamine metabolism

Cited by 54 publications

References 88 publications

Involvement of Carrier-Mediated Transport at the Blood–Cerebrospinal Fluid Barrier in Spermine Clearance from Rat Brain

Involvement of Carrier-Mediated Transport at the Blood–Cerebrospinal Fluid Barrier in Spermine Clearance from Rat Brain

Cell-autonomous circadian clock of hepatocytes drives rhythms in transcription and polyamine synthesis

Identification of a Novel Aminopropyltransferase Involved in the Synthesis of Branched-Chain Polyamines in Hyperthermophiles

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