A model of human phenylalanine metabolism in normal subjects and in phenylketonuric patients

Kaufman, Seymour

doi:10.1073/pnas.96.6.3160

Cited by 98 publications

(78 citation statements)

References 35 publications

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“…The increased production of 2-phenylethylamine might reflect metabolic or dietary differences in the carnivore order. 2-phenylethylamine is a metabolite of phenylalanine, an essential amino acid found in dietary protein (20). One attractive model to explain our data is that elevated levels of dietary protein in meateating species directly lead to enhanced 2-phenylethylamine levels in urine.…”

Section: Discussionmentioning

confidence: 92%

Detection and avoidance of a carnivore odor by prey

Ferrero

Lemon²,

Fluegge³

et al. 2011

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

310

305

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Predator-prey relationships provide a classic paradigm for the study of innate animal behavior. Odors from carnivores elicit stereotyped fear and avoidance responses in rodents, although sensory mechanisms involved are largely unknown. Here, we identified a chemical produced by predators that activates a mouse olfactory receptor and produces an innate behavioral response. We purified this predator cue from bobcat urine and identified it to be a biogenic amine, 2-phenylethylamine. Quantitative HPLC analysis across 38 mammalian species indicates enriched 2-phenylethylamine production by numerous carnivores, with some producing >3,000-fold more than herbivores examined. Calcium imaging of neuronal responses in mouse olfactory tissue slices identified dispersed carnivore odor-selective sensory neurons that also responded to 2-phenylethylamine. Two prey species, rat and mouse, avoid a 2-phenylethylamine odor source, and loss-of-function studies involving enzymatic depletion of 2-phenylethylamine from a carnivore odor indicate it to be required for full avoidance behavior. Thus, rodent olfactory sensory neurons and chemosensory receptors have the capacity for recognizing interspecies odors. One such cue, carnivore-derived 2-phenylethylamine, is a key component of a predator odor blend that triggers hard-wired aversion circuits in the rodent brain. These data show how a single, volatile chemical detected in the environment can drive an elaborate danger-associated behavioral response in mammals.kairomone | olfaction | pheromone | trace amine-associated receptors | G protein-coupled receptor P redator-prey relationships provide a classic paradigm for understanding the molecular basis of complex behavior (1). Predator-derived visual, auditory, and olfactory cues induce hardwired defensive responses in prey that are sculpted by strong evolutionary pressure and are critical for survival. For example, odors from felines, canines, and other predators elicit innate reactions in rodents, including stereotyped avoidance behaviors and stimulation of the hypothalamic-pituitary-adrenal axis that coordinates sympathetic stress responses (1). Aversive reactions to odors can function in reverse as well, as skunk thiols facilitate prey escape by repelling predator species (2).Predator odors contain a class of ecological chemosignals termed kairomones, cues transmitted between species that benefit the detecting organism. Predator odor-derived kairomones that elicit defensive responses in rodents are largely unknown and can be found in fur, dander, saliva, urine, or feces of divergent predator species. One volatile chemical produced by foxes, 2,5-dihydro-2,4,5-trimethylthiazole (TMT), and two nonvolatile lipocalins produced by cats and rats elicit fear-like or aversive behavior in mice, enabling remote or contact-based detection of predator cues (3-5). Each of these chemicals is not broadly produced by predators, raising the possibility that rodents detect a multitude of species-specific predator signals, each of which triggers a hardwir...

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Section: Discussionmentioning

confidence: 92%

Detection and avoidance of a carnivore odor by prey

Ferrero

Lemon²,

Fluegge³

et al. 2011

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

310

305

View full text Add to dashboard Cite

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“…These are SAM [29][30][31][32], phosphoethanolamine Nmethyltransferase 1 (Wu et al 2007), cytochrome oxidase c (Zikos et al 2014;Tine et al 2011), and calcineurin B Gu et al 2008). Other enzyme genes have functions in anoxic response (alcohol acetyltransferase) (Kwast et al 2002), disease responses (phenylalanine hydroxylase and polypeptide N-acetylgalactosaminyltransferase 2) (Kaufman 1999) and stress responses (RNA polymerase II) (Bourbonnais et al 2001). These results indicate that miRNA play important roles in responding to low salinity stress through a series of enzymatic reactions that are highly efficient and have a low energy consumption.…”

Section: Discussionmentioning

confidence: 99%

The identification and characteristics of salinity-related microRNAs in gills of Portunus trituberculatus

Liu

Gao

et al. 2016

Cell Stress and Chaperones

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MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate gene expression in organisms. To understand the underlying mechanisms behind the molecular response of the crab to low salt-stress, highthroughput Illumina/Solexa deep sequencing technology was used to investigate the expression profiles of miRNAs under low salinity challenged. Two mixed RNA pool libraries of gill tissues from low salinity challenged (LC) and the control groups (NC) were sequenced on the Illumina platform. A total of 6,166,057 and 7,032,973 high-quality reads were obtained from the NC and LC libraries, respectively. Sixty-seven miRNAs consisting of 16 known and 51 novel ones were identified, among which, 12 miRNAs were differentially expressed in LC compared to NC. Thirty-four of the target genes predicted were differentially expressed in the opposite direction to the miRNAs, which were involved in crucial processes related to osmoregulation by gene ontology (GO) functional enrichment analysis, such as anion transport processes (GO:0006820) and chitin metabolic process (GO:0006030). These results provide a basis for further investigation of the miRNA-modulating networks in osmoregulation of Portunus trituberculatus.

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“…Elevation of serum Phe inhibits enzymes important in the conversion of tyrosine and tryptophan to their respective neurotransmitter derivatives, affecting catecholamine metabolism in the brain (Kaufman, 1999;Puglisi-Allegra et al, 2000). For this reason, we chose to evaluate the nigrostriatum of Pah enu2 mice for pathologic changes that may occur secondary to monoaminergic metabolic alterations.…”

Section: Introductionmentioning

confidence: 99%

PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pahenu2 mice

et al. 2007

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Phenylketonuria (PKU) is a common genetic disorder in humans that arises from deficient activity of phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine to tyrosine. There is a resultant hyperphenylalanemia with subsequent impairment in cognitive abilities, executive functions and motor coordination. The neuropathogenesis of the disease has not been completely elucidated, however, oxidative stress is considered to be a key feature of the disease process. Hyperphenylalanemia also adversely affects monoaminergic metabolism in the brain. For this reason we chose to evaluate the nigrostriatum of Pah enu2 mice, to determine if alterations of monoamine metabolism resulted in morphologic nigrostriatal pathology. Furthermore, we believe that recent developments in adeno-associated virus (AAV)-based vectors have greatly increased the potential for long-term gene therapy and may be a viable alternative to dietary treatment for this metabolic disorder. In this study we identified neurodegenerative changes with regenerative responses in the nigrostriatum of Pah enu2 mice that are consistent with oxidative injury and occurred as early as 4 weeks of age. These neuropathologic changes were reversed following portal vein delivery of a recombinant adeno-associated virus-mouse phenylalanine hydroxylase-woodchuck hepatitis virus post-transcriptional response element (rAAV-mPAH-WPRE) vector to Pah enu2 mice and corresponded to rapid reduction of serum Phe levels.

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A model of human phenylalanine metabolism in normal subjects and in phenylketonuric patients

Cited by 98 publications

References 35 publications

Detection and avoidance of a carnivore odor by prey

Detection and avoidance of a carnivore odor by prey

The identification and characteristics of salinity-related microRNAs in gills of Portunus trituberculatus

PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pahenu2 mice

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