beta-phenylethylamine, a small molecule with a …...decarboxylation product of phenylalanine...

Article ID: WMC004459 ISSN 2046-1690

Beta-phenylethylamine, a small molecule with alarge impactPeer review status:Yes

Corresponding Author:Ms. Meredith Irsfeld,Fargo, North Dakota State University - United States of America

Submitting Author:Dr. Birgit Pruess,Associate Professor, North Dakota State University, Fargo ND 58108, 58108 - United States of America

Other Authors:Mr. Matthew Spadafore,Fargo, North Dakota State University - United States of America

Previous Article Reference: http://www.webmedcentral.com/article_view/4409

Article ID: WMC004459

Article Type: Review articles

Submitted on:12-Dec-2013, 07:13:25 PM GMT Published on: 13-Dec-2013, 06:22:50 AM GMT

Article URL: http://www.webmedcentral.com/article_view/4459

Subject Categories:BIOCHEMISTRY

Keywords:neurotransmitter, antimicrobial, food spoilage

How to cite the article:Irsfeld M, Spadafore M, Pruess B. Beta-phenylethylamine, a small molecule with a largeimpact. WebmedCentral BIOCHEMISTRY 2013;4(12):WMC004459

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1R15AI089403 from NIH/NIAID

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The authors declare no competing interets.

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Beta-phenylethylamine, a small molecule with alarge impactAuthor(s): Irsfeld M, Spadafore M, Pruess B

Abstract

During a screen of bacterial nutrients as inhibitors ofEscherichia coli O157:H7 biofilm, the Prub researchteam made an intriguing observation: among 95carbon and 95 nitrogen sources tested, β-phenylethylamine (PEA) performed best at reducingbacterial cell counts and biofilm amounts, whensupplemented to liquid beef broth medium (Lynnes etal., 2013a). This review article summarizes what isknown about PEA.

After introducing the chemistry of the molecule, thisstudy focuses on PEA as a neurotransmitter and thenmoves on to its role in food processing, beforedetailing the reduction of bacterial cell counts andbiofilm amounts. Comparisons to biogenic amines arepresented. Briefly, PEA is a trace amine whosemolecular mechanism of action differs from biogenicamines, such as serotonin or dopamine. Especiallylow or high concentrations of PEA may be associatedwith specific psychological disorders. For thosedisorders that are characterized by low PEA levels (e.g. attention deficit hyperactivity disorder), PEA hasbeen suggested as a ‘safe’ alternative to drugs, suchas amphetamine or methylphenidate, which areaccompanied by many undesirable side effects.

In food, PEA and other biogenic amines can bedetected as a result of microbial metabolism. As aconsequence, these chemicals can be used asindicators of bacterial contamination. Intriguingly, PEAcan be found in chocolate, where it is a result of thethermal processing of the CACAO. As a conclusion ofthis brief review, we will present our own evidence ofPEA as an inhibitor of biofilm formation and celldivision through a modulation of gene expression.

Introduction

ß-phenylethylamine (PEA) is a small molecule thatexhibits an array of intriguing and seemingly unrelatedfunctions. The purpose of this review is to summarizegeneral information about PEA as well as detailing aselection of the functions, namely its role as aneurotransmitter and in food processing. Since PEA isa member of the trace amines which are structural and

functional relatives of biogenic amines, we presentinformation on other trace amines and biogenicamines as appropriate. General information aboutPEA is summarized in Chapter I, including thechemical properties of PEA (1.1), its naturaloccurrence and biological synthesis (1.2), and itschemical synthesis (1.3). Chapter II describes PEA’sfunctions as a neurotransmitter in three examples ofpsychological disorders: hyper attention deficithyperactivity disorder (2.1), depression (2.2), andschizophrenia (2.3). A comparison of PEA’s action tothat of other trace and biogenic amines is provided inthis Chapter (Illustration 3). Finally, Chapter IIIdescribes the role of PEA in food processing, startingwith its occurrence in fermented food and meat as aresult of microbial metabolism (3.1), and followed byits occurrence in chocolate as a result of thermalprocessing (3.2). The article concludes with therecently described use of PEA as a modulator of geneexpression to reduce biofilm amounts and bacterialcell counts (3.3).

Review

General Information

1.1 Chemical Properties of PEA

PEA is known under a variety of names including β-phenylethylamine, β-phenethylamine, andphenylethylamine. According to the International Unionof Pure and Applied Chemistry (IUPAC), the propername of PEA is 2-phenylethylamine. Its molecularformula is denoted by C8H11N.

The general information on and the chemicalproperties of PEA are summarized in Illustration 1.Briefly, PEA has a molecular weight of 121.17964g/mol, a high solubility in ddH2O (Cashin, 1972;Shannon et al., 1982), and a short half-life (Shannonet al., 1982). These chemical characteristics impactPEA’s biological functions. In particular, the lack of amethyl group distinguishes PEA from its structuralrelative, amphetamine.

1.2 Natural Occurrence and Biological Synthesisof PEA

The occurrence of PEA and its derivatives haspreviously been reviewed (Bentley, 2006). PEA canbe found in many algae (Guven et al., 2010), fungi and



bacteria (Kim et al., 2012) as well as a variety ofdifferent plant species (Smith, 1977). PEA is thedecarboxylation product of phenylalanine (Illustration2A).

Two proposed mechanisms for amino aciddecarboxylation are a pyridoxal phosphate dependentreaction and a non-pyridoxal phosphate dependentreaction. The reactions differ in the starting residue;the first reaction utilizes a pyridoxal-5-phosphate andthe latter uses a pyruvoyl residue. The free aminoacids needed for this decarboxylation may be providedby bacterial proteolysis (Shalaby, 1996). In severalbacterial species, the decarboxylation is catalyzed bythe enzyme tyrosine decarboxylase, which alsoconverts tyrosine to another trace amine, tyramine(Marcobal et al., 2012; Pessione et al., 2009).Intriguingly, PEA synthesized by fungi and bacteriacan also be found in food products (Onal et al., 2013),where it serves as an indicator of food quality andfreshness. Such foods include the Korean natto (Kimet al., 2012) and commercial eggs (Figueiredo et al.,2013). Another food that contains PEA is chocolate,where it is not produced by bacteria, but during thethermal processing of cocoa (Granvogl et al., 2006).PEA can also be found in members of the familyLeguminosae, which is the second-largest family ofseed plants and is comprised of trees, shrubs, vines,herbs (such as clover), and vegetables (such as beansand peas). The various different species found withinthis family have been used as food, green manure,and for medicinal purposes (Sanchez-Blanco et al.,2012). Smith and coworkers hypothesized that plantsynthesized PEA may serve as a defense mechanismagainst insects and foraging animals (Smith, 1977).

PEA has also been found in the brains of humans andother mammals (Paterson et al., 1990; Philips et al.,1978). This is attributed to the high solubility of PEA inplasma and its ability to cross the blood-brain barrier(Oldendorf, 1971). Like its α-methylated derivative,amphetamine, PEA has stimulant effects which lead tothe release of so called biogenic amines, includingdopamine and serotonin (Bailey et al., 1987; Rothman& Baumann, 2006). Unlike amphetamine, PEA israrely found in high concentrations in the human body,due to its oxidative deamination to phenylacetic acidby the enzyme B monoamine oxidase (MAO) (Yang &Neff, 1973). Phenylacetic acid has an effect that issimilar to the activity of the natural endorphins, aneffect that is known as a “runner’s high”.

Due to its impact on the levels of several ‘feel goodhormones’ (see above), PEA has recently gainedpopularity as a nutritional supplement that is sold bynumerous health stores to improve mood. Since it also

decreases the amount of water intake, it aids weightloss efforts (Hoffman et al., 2006). Altogether, PEAappears to have a number of positive effects onhuman health without the risks of its structuralrelatives.

1.3 Chemical Synthesis of PEA

Two different pathways that lead to the chemicalsynthesis of PEA have been established in the 1940sand 1950s. First, PEA is produced by reduction of anitrile into an amine (Robinson & Snyder, 1955).Specifically, benzyl cyanide is mixed with theRaney-Nickel catalyst in a calorimeter bomb. Theformation of secondary amines in this reaction isreduced by the addition of ammonia. The reactionoccurs at 13.9 Mpa and 130oC under hydrogen. Thecooled down liquid is removed from the catalyst byfiltration. This procedure has a yield of 83 to 87%.

A second, simpler way of producing PEA is to reducew-nitrostyrene with lithium aluminum hydride in ether(NYSTROM & BROWN, 1948) (Illustration 2B). Theexperimental procedure that employs the use oflithium aluminum in reduction reactions follows themechanism used in a Grignard synthesis.w-nitrostyrene is added to the previously preparedlithium aluminum hydride in ether while stirring. Thisresults in an alcoholate precipitate, which thickens thesolution, requiring more ether to be added. Finally,using acid hydrolysis, the metal alcoholate isdecomposed and the product can be isolated andextracted from the ether.

Recent literature focuses on the biological synthesis ofP E A , r a t h e r t h a n t h e c h e m i c a l o n e .1-phenylethylamine can be synthesized byEscherichia coli overexpressing ω-transaminase(Cardenas-Fernandez et al., 2012). Likewise, the PEAbiosynthetic enzyme from Enterococcus faecium canbe expressed in E. coli, which leads to large amountsof L-phenylalanine and tyrosine decarboxylase activity(Marcobal et al., 2006). Intriguingly, PEA can serve asa substrate for the synthesis of other drugs, such assulfonamides that are being used as anti-microbials(Rehman et al., 2012).

II. PEA as a Neurotransmitter

PEA is a member of the so-called trace amines(reviewed by Premont et al., 2001). The expression“trace amine” is used to refer to a group of amines thatoccur at much lower intra- and extra-cellularconcentrations than the chemically and functionallyrelated biogenic amines and neurotransmittersepinephrine, norepinephrine, serotonin, dopamine,and histamine. The molecular mechanism of the traceamines involves binding to a novel G protein-coupled



receptor, called TAAR (trace amine-associated receptor) (Borowsky et al., 2001; Bunzow et al., 2001),the most studied of which, TAAR1, can be activated bythe drug amphetamine as well (Borowsky et al., 2001).The downstream events that follow the initialinteraction of PEA and TAAR1 are not nearly as wellunderstood as the receptors and their various ligandsthemselves (Zucchi et al., 2006); it is howeverbelieved that binding of PEA to TAAR1 results in analteration of the monoamine transporter functions,which leads to inhibition of the re-uptake of dopamine,serotonin, and norepinephrine (Xie & Miller, 2008).Eventually, this will cause an increased concentrationof these neurotransmitters at the synapses. A similarincrease in the synaptic concentrations of dopaminecan be accomplished by blocking the dopaminetransporter directly. Methylphenidate is an example ofa class of drugs that can perform this blockage (Gatleyet al., 1999).

The chemical properties of the biogenic amines, traceamines, and structurally related drugs are summarizedin I l lustration 3. I l lustration 4 is a graphicrepresentation of the regulatory pathway from thetrace amine PEA to the increased concentration of thebiogenic amines and neurotransmitters dopamine andserotonin. The effects of the drugs amphetamine andmethylphenidate are included. Chapter II summarizesthe impact of PEA on three psychological disorders,attention deficit hyperactivity disorder, depression, andschizophrenia.

2.1 Attention deficit hyperactivity disorder

A common disease that an estimated 4-9% of youngchildren suffer from is attention deficit hyperactivedisorder (ADHD) (reviewed by Cormier, 2008). ADHDis a chronic childhood disorder, which is characterizedby a number of behavioral symptoms, including asmall attention span, increased frustration,distractibility, and often depression and anxiety(American Psychiatric Association, 2000). ADHD oftenis paralleled by co-existing psychiatric disorders andpatients can have problems that are attributable toADHD way into their adulthood (Brassett-Harknett &Butler, 2007). Diagnosis of ADHD has traditionallybeen done by analysis of the symptoms (AmericanPsychiatric Association, 2000). However, this has ledto misdiagnosis and, consequently, overmedication.Having a biomarker, in conjunction with a symptomaticdiagnosis, could reduce such misdiagnosis and/orovermedication. PEA was recently described as thefirst such biomarker for ADHD (Scassellati et al.,2012). Specifically, the urinary output of PEA waslower in a population of children suffering from ADHD,as compared to the healthy control population, an

observation that was paralleled by reduced PEA levelsin ADHD individuals (Baker et al., 1991; Kusaga,2002). In a consecutive study (Kusaga et al., 2002),those of the children suffering with ADHD were treatedwith methylphenidate, also known as Ritalin. Patientswhose symptoms improved in response to treatmentwith methylphenidate had a significantly higher PEAlevel than patients who did not experience such animprovement in their condition (Kusaga et al., 2002).

While this is encouraging, amphetamine andmethylphenidate based drugs demonstrate manyundesirable side effects, including mild headaches,nausea, insomnia, and constipation. Overdose,whether accidental or intentional, of any of theamphetamine or methylphenidate drugs has beenassociated with cardiovascular effects, which wereattributed to increased levels of extracellular dopamine,norepinephrine, and serotonin (Spiller et al., 2013).While the connection between stimulant drugs as atreatment for ADHD and cardiovascular disease at thistime still appears controversial (Olfson et al., 2012),naturopathic professionals have started to recommendPEA as a treatment for ADHD because of theassumed lack of side- and long-term effects.

2.2 Depression

Depression is a very common, sometimes seriousdisease that affects a wide range of people. It iscurrently the second leading cause of disability in 15 to44 year olds. It is predicted that by the year 2030,depression will be the primary cause of disability(World Health Association, 2008). While depressionmay be most common in the age group of 15 to 44, itcan affect people of all ages and backgrounds. Amongthe characteristics of depression that weresummarized in a review article (Voinov et al., 2013),women are 50% more likely to be affected bydepression than men and depression can shorten aperson’s life by 25-30 years (Voinov et al., 2013).

Most medication that is currently available is about80% effective for those suffering from depression(Voinov, 2013). Selective serotonin re-uptakeinhibitors (SSRI) are the most popular antidepressantprescribed worldwide (Artigas, 2013). SSRI functionby blocking the serotonin transporter and thusinhibiting the re-uptake of serotonin (Gutman & Owens,2006; Peremans et al., 2006). This will result in anincrease of the synaptic concentration of serotonin(see Illustration 4). However, SSRI act very slowly atthe beginning of the treatment, while exhibiting arange of side effects upon long term use. Theselong-term side effects include insulin resistance (Chenet al., 2012), bone density loss (Haney et al., 2007),and some poorly understood effects on the offspring



of mothers with maternal depression (Olivier et al.,2013). Although scientists question the next step inthis research (Artigas, 2013), it is clear that novelapproaches to depression treatment must bedeveloped. The study by Xie and Miller (Xie & Miller,2008), which had shown that PEA altered theserotonin transporter by interacting with TAAR, maypoint towards a safer alternative to SSRI treatment ofdepression in the form of PEA.

2.3 Schizophrenia

Schizophrenia is a rare mental disorder that couldpotentially be related to PEA. About 1% of the world’spopulation is affected by schizophrenia, which ischaracterized by problematic thinking and perception(Rossler et al., 2005). Typically, schizophrenia startsaround adolescence and will stay with the patients forthe rest of their lives, though life expectancy can belargely reduced due to suicide. An additionalcomplication is community attitude because manypeople perceive schizophrenic patients as potentiallydangerous (Stuart & Arboleda-Florez, 2001).

There are different ideas on how one developsschizophrenia. One hypothesis proposes thatdopamine contributes to the development ofschizophrenia (Howes & Kapur, 2009). In agreementwith this hypothesis, patients suffering fromschizophrenia are hyper-sensitive to drugs (e.g.methylphenidate) that block the dopamine receptor(Lieberman et al., 1987). A new perspective is givenby the TAAR1 receptor (Illustration 4). TAAR1activation improves the symptoms that are associatedwith both schizophrenia and depression (in rodent andprimate models), without causing the range ofnegative effects that result from direct blockage of thedopamine receptor (Revel et al., 2013).

Among other factors that may contribute toschizophrenia are inflammatory cytokines (Zakharyan& Boyajyan, 2013) and phospholipase (Koh, 2013) .Altogether, schizophrenia may be the most complex ofthe psychological disorders discussed in this studyand it is quite apparent that many factors contribute toits development.

III. PEA and other Amines in Food

PEA is connected to food processing in several,seemingly unrelated ways. First, PEA and otheramines can be found in food as a result of themetabolic activity of bacteria (3.1). As a consequenceof this, PEA can be used as a biomarker forcontamination of food by the respective bacteria. Asecond process which does not involve bacterialmetabolism can lead to the production of PEA inchocolate through the thermal processing of cocoa

(3.2). Finally, research by our own lab has shown thatPEA can be added to food intentionally to modulategene expression which will lead to phenotypes that areless harmful to humans. Two such phenotypes are areduction in biofilm amounts and reduced bacterial cellcounts of E. coli O157:H7 (3.3).

3.1 PEA and other amines in food as a result ofmicrobial contamination

Some foods that contain microorganisms can releasehigh levels of amines, including the trace amines PEA,tyramine, and tryptamine, the biogenic aminehistamine, and the polyamines putrescine andcadaverine (Shalaby, 1996). Such amines are formedby bacteria of the genera Lactobacillus, Clostridium,Pseudomonas, and Enterobacteriaceae that containamino acid decarboxylases, which remove an α-carboxyl group from the respective amino acid(Giraffa, 2003; Shalaby, 1996).

This increased concentration of amines is due tobacterial metabolic processes and is commonlyassociated with foods and food products madethrough the process of fermentation (Bunkova et al.,2013). A good example of this is the “cheesereaction”, which refers to high levels of tyramine as aresult of elevated levels of tyrosine in cheese that hashad increased storage times at temperatures higherthan recommended by the producer. As mentionedearlier (Chapter 1.2), PEA can be a by-product of thetyrosine decarboxylase reaction because the sameenzyme that is capable of converting tyrosine totyramine can also metabolize phenylalanine to PEA(Marcobal et al., 2012). In individuals takingmonoamine oxidase inhibiting drugs, the ‘cheesereaction’ can result in a hypertensive crisis (Boulton etal., 1970; Da et al., 1988; Deftereos et al., 2012).

A second group of food or food product that containselevated levels of amines is meat and/or fish (Kulawiket al., 2013; Li et al., 2012; Liu et al., 2013), whereamine production is part of the food spoilage reactionand can be used as an indicator of food freshness andquality. Specifically, bacteria from the familiesEnterobacteriaceae and Pseudomonadaceae canproduce cadaverine and putrescine in spoiled turkeymeat. Fraqueza and coworkers suggested to usetyramine, putrescine, and cadaverin to quantify meatfreshness (Fraqueza et al., 2012). In vegetables, highlevels of tyramine were only seen in brine, unless thevegetables were contaminated prior to processing orthe temperature and storage time were extreme(Moret et al., 2005).

Since elevated levels of amines are usually anindicator of food spoilage, it is possible to use



detection of amines as an indicator of food freshness.One such technique is thin-layer chromatography toseparate and identify amounts of tyramine and PEA(Garcia-Moruno et al., 2005).

3.2 PEA in chocolate as a result of thermalprocessing

The connection between “food and mood” wasrecognized long time ago (Ottley, 2000). In particular,chocolate craving has been the focus of intenseresearch (Durkin et al., 2012; Hormes & Timko, 2011;Werthmann et al., 2013). Lately, the combination ofchocolate with coffee has been proposed as “a novelelixir for a long and happy life” (Dal Moro, 2013).Besides a number of other beneficial substances (e.g.antioxidants), chocolate also contains trace amountsof PEA (Ziegleder et al., 1992), a result of the thermalprocessing and fermentation of cocoa (Granvogl et al.,2006). Since we mentioned earlier that PEA ispromoted to aid weight loss, one may conclude that ifa person eats enough chocolate they will lose weight!Careful readers, please note: in a study that attemptedto determine the concentration of PEA in chocolate,the detection limit for PEA was 3 mg/kg of chocolateand the concentration of PEA in their chocolatesamples was below this limit (Pastore et al., 2005). Incontrast, the recommendation for PEA as a nutritionalsupplement is currently 500 mg/day (for an example,please, see http://www.bodybuilding warehouse.com).This means that the concentration of PEA in chocolateis not high enough to induce weight loss, so eatingchocolate will still lead to weight gain.

One interesting controversy around chocolate andPEA is the question of whether chocolate can causemigraine and whether this may be due to PEA. Ofcourse, food in general can trigger migraine (Finocchi& Sivori, 2012). Also, individual studies point towardschocolate as one of those foods (Fukui et al., 2008),but other studies are in contrast with these findings(Marcus et al., 1997). The fact that other foods thatcontain PEA, tyramine, or histamine (e.g. cheese andwine) may also trigger migraine (Werthmann et al.,2013) raised the question whether dietary amines maybe responsible for this response. This question isjustified, considering that PEA causes the release ofnor-epinephrine into the synaptic space, whichconsequently constricts the aorta and the coronaryarteries (Broadley et al., 2009). However, resultsamong various studies are inconclusive (Jansen et al.,2003), and the connection between chocolate andmigraines remains a mystery.

3.3 PEA as a modulator of bacterial geneexpression

In Chapter 3.1, we discussed contamination and foodspoilage by bacteria. One such initially contaminatedfood can cross-contaminate additional food productsthrough the food processing chain because of thebacteria’s ability to attach to food contact surfaces andform biofilm (Giaouris et al., 2013).

Recent research advances that are aimed at theprevention of biofilm include the manipulation of thebacteria’s signal transduction pathways, includingquorum sensing (Bassler, 2010) and two-componentsignaling (Lynnes et al., 2013b). One suchenvironmental signal that bacteria can respond to isPEA, whose signal transduction pathway may includethe flagellar and global regulator complex FlhD/FlhC(Stevenson et al., 2013). A reduction in flagellasynthesis would be expected to inhibit the first phaseof biofilm formation, reversible attachment. In our ownresearch lab (Lynnes et al., 2013a), PEA was the mostinhibitory of the 95 carbon and 95 nitrogen sourcesscreened for their effect on E. coli O157:H7 growth,bacterial cell counts, and biofilm amounts. In liquidbeef broth medium, PEA reduced biofilm amounts.Intriguingly, bacterial cell counts were reduced at thesame time and with a similar inhibitory concentration.In contrast, the effect of PEA on bacterial growth, asmeasured by the optical density of the culture, wasaffected only at a much higher concentration of PEA.In a final experiment, bacterial cell counts of E. coliO157:H7 were determined from beef meat pieces thatwere treated with different dilutions of PEA andsubsequently inoculated with the bacteria; this resultedin a 90% reduction of bacterial cell counts when thebeef was treated with a concentration of PEA at 150mg/ml. We were unable to determine biofilm formationon the beef meat pieces. Altogether, this studydemonstrated how PEA could be used to alter geneexpression in order to reduce biofilm formation andbacterial cell counts (Lynnes et al., 2013a). Thequestion arises whether it could be possible tointegrate PEA into novel biomaterials that can then beused to coat food processing equipment to preventbiofilm formation on such equipment and crosscontamination during the food processing chain.

Acknowledgement(s)

The authors thank the NIH/NIAID for funding B.M.P.through grant 1R15AI089403. Dr. Shelley Horne(NDSU) and Jessica Ebert (NDSU) are thanked forcritically reading the manuscript and helpfuldiscussions. Laura Nessa (NDSU) is thanked forhelpful discussions and valuable ideas.



Authors Contribution(s)

All authors contributed equally to the work.

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Solvent independentproperties Solvent dependent properties Reference

In ddH2O In lipid In Plasma

Alternativenames

phenylethylamine, β-phenylethylamine,2-phenylethylamine,benzeneethanamine,

phenethylamine,β-phenethylamine, 2-phenethylamine

NA NA NA http://pubchem.ncbi.nlm.nih.gov

MolecularFormula C8H11N NA NA NA http://pubchem.nc

bi.nlm.nih.govMolecularweight 121.17964 g/mol NA NA NA http://pubchem.nc

bi.nlm.nih.govCompaniesthat sellPEA

Forest Health,Vitacost, Amazon,

Walmart

NA NA NA NA

Toxicity Mouse LD50 (oral)400 mg/kg

NA NA NA MSDS, TCIAmerica

Solubility NA Highsolubility

Lowsolubility

Highsolubility

MSDS, TCI(Cashin, 1972), (Shannon et al.,

1982)

Half life NA NA NA ~5-10min (Shannon et al.,1982)

Illustrations

Illustration 1

Table 1



Illustration 2

Figure



I. Biogenic Amines

Name Structure Synthesizedfrom:

Functions

Dopamine L-Tyrosine CNS: regulates movement

Blood vessels: vasodilation

Serotonin L-Tryptophan CNS: mood, sleep, memory, andlearning

Gut: intestinal movement

Histamine Histidine CNS: sleep

Immune system: inflammatoryresponse (allergy)

Epinephrine(Adrenaline)

Tyrosine viadopamine andnor-epinephrine

CNS: stress response (fight or flight)

Blood vessels: vasoconstriction

Nor-epinephrine(Nor-adrenaline)

Tyrosine viadopamine

CNS: heart contractions (heart rate),vascular tone (blood pressure)

Illustration 3

Properties and functions of biogenic amines, trace amines and structurally related drugs



II. Trace Amines


Protein Targets

ß-phenyl-ethylamine (PEA)

L-Phenylalanine TAAR1

p-Tyramine L-Tyrosine TAAR1; dopamine receptor

Tryptamine L-Tryptophan 5-hydroxytryptamine receptor;NFκB1; Cytochrome P450

Octopamine Tyrosine viatyramine

TAAR1

III. Structurally related Drugs


Function

Amphetamine Ephedrine A stimulant of the central nervoussystem that mimics the effects ofdopamine, epinephrine, andnorepinephrine.



Methyl-phenidate Piperidinederivative

A stimulant of the central nervoussystem that are used to treat attentiondeficit disorders and narcolepsy.



Illustration 4

Fig 4



Reviews

Review 1

Review Title: AcceptablePosted by Dr. Oluyomi S Adeyemi on 13 Dec 2013 10:05:53 AM GMT

1 Is the subject of the article within the scope of the subject category?

2 Are the interpretations / conclusions sound and justified by the data?

3 Is this a new and original contribution?

4 Does this paper exemplify an awareness of other research on the topic?

5 Are structure and length satisfactory?

6 Can you suggest brief additions or amendments or an introductory statement that will increase thevalue of this paper for an international audience?

7 Can you suggest any reductions in the paper, or deletions of parts?

8 Is the quality of the diction satisfactory?

9 Are the illustrations and tables necessary and acceptable?

10 Are the references adequate and are they all necessary?

11 Are the keywords and abstract or summary informative?

Rating: 0

Comment: N/A

Competing interests: N/A

Invited by the author to make a review on this article? : Yes

Experience and credentials in the specific area of science: N/A

Publications in the same or a related area of science: No

References: N/A

How to cite: Adeyemi O.Acceptable[Review of the article 'Beta-phenylethylamine, a small molecule with a largeimpact ' by ].WebmedCentral 1970;4(12):WMCRW002905


http://http://www.webmedcentral.com/Article_Review_View/2905


Review 2

Previous Version: A-phenylethylamine, a small molecule with a large impact Review Title: A-Phenylalanine, a small molecules with a large impactPosted by Dr. Ranjith N Kumavath on 29 Oct 2013 10:09:17 AM GMT












Rating: 1

Comment: As the whole this paper is noting speacking much novel or new information. hence i woould not recommand thisms for final considaration.

Competing interests: None


Publications in the same or a related area of science: Yes

References: Catabolism of L-phenylalanine in research in microbiology,2007

How to cite: Kumavath R.A-Phenylalanine, a small molecules with a large impact[Review of the article'Beta-phenylethylamine, a small molecule with a large impact ' by ].WebmedCentral 1970;4(10):WMCRW002882


http://http://www.webmedcentral.com/article_view/4409



Review 3

Review Title: A-phenylethylamine, a small molecule with a large impactPosted by Dr. Oluyomi S Adeyemi on 17 Oct 2013 03:36:20 PM GMT












Rating: 7

Comment: Generally, review articles are written with explicity. It usually discusses existing scientific findings on a particularsubject with a view to apprpriating 'what has been done' and 'what is yet to be done'. It essentially identifies andarticulates research or knowledge gaps from available empirical data which could become potential areas forresearch exploration. The current article has not fared well in this direction.



Experience and credentials in the specific area of science: I am an academic biochemist


How to cite: Adeyemi O.A-phenylethylamine, a small molecule with a large impact[Review of the article'Beta-phenylethylamine, a small molecule with a large impact ' by ].WebmedCentral 1970;4(10):WMCRW002876




Review 4

Review Title: A-phenylethylamine, a small molecule with a large impactPosted by Dr. Miranda Bader on 10 Oct 2013 08:57:48 PM GMT












Rating: 2

Comment: 1. Needs to be proof-read, not the best English grammar and flow.2. Please ensure files are saved and uploaded in compatible formats -- "?-methylated".3. It is not an “illustration” if it is a table.4. Specifically, 1 kg of benzyl cyanide is mixed with 1 tablespoon of the Raney-Nickel catalyst in a calorimeterbomb. – Because chemical recipes are relative to the scientist and their experiment, it should not be included in areview.5. “Serenity Station describes the effects of PEA as ‘feeling happier, more alive and even having a better moodand attitude’” – This this is an advertisement, not peer-reviewed, proven research, and therefore should not beincluded in this manuscript. Furthermore, it is stated that “Throughout this manuscript, we mention companiesthat sell PEA. We are not in any way affiliated with any of these and do not mean to discriminate. The list ofcompanies is incomplete and exemplary.” This good to state up-front, however, the company information thatwas included was not really useful. How were the companies that were included in the manuscript selected? Itwould be better to include a comprehensive review of peer-reviewed, previously published literature.6. Because PEA is legume-, bacterial-, and chocolate-derived, AND since “…PEA has stimulant effects whichlead to the release of so called biogenic amines,… PEA has recently gained popularity as a nutritionalsupplement that is sold by numerous health stores to improve mood,” it seems counterintuitive to use it as anindicator of bacterial contamination and spoilage. Elaborate on and clarify this conundrum. Furthermore, it isstated that, “Most recently, it has been found that PEA can be added to food intentionally to reduce bacterial cellcounts of E. coli O157:H7 (3.3).” – Can it be concluded then that a higher amount of naturally occurring PEA isindicative of lower amounts of bacterial contamination/spoilage?7. Since elevated levels of amines are usually an indicator of food spoilage, it is possible use detection of aminesas an indicator of food freshness. – Other amines, yes, but you do not provide evidence of PEA indicative ofspoilage?



Experience and credentials in the specific area of science: PhD research in neurochemistry, specifically brain



http://www.webmedcentral.com/_wmccp/edit_user/5813



How to cite: Bader M.A-phenylethylamine, a small molecule with a large impact[Review of the article'Beta-phenylethylamine, a small molecule with a large impact ' by ].WebmedCentral 1970;4(10):WMCRW002874



Review 5

Review Title: A-phenylethylamine, a small molecule with a large impactPosted by Dr. L. Caetano M Antunes on 06 Oct 2013 02:57:16 AM GMT












Rating: 7

Comment: In general, the paper is well written and brings forth an interesting subject.



Experience and credentials in the specific area of science: I currently perform small molecule research myself.


How to cite: Antunes L.A-phenylethylamine, a small molecule with a large impact[Review of the article'Beta-phenylethylamine, a small molecule with a large impact ' by ].WebmedCentral 1970;4(10):WMCRW002872



beta-phenylethylamine, a small molecule with a …...decarboxylation product of phenylalanine...

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