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AdvNutr.2010Nov1(1):3137.

PMCID:PMC3042786

Publishedonline2010Nov16.doi:10.3945/an.110.1008

FunctionalAminoAcidsinGrowth,Reproduction,andHealth1,2
GuoyaoWu*
DepartmentofAnimalScienceandFacultyofNutrition,TexasA&MUniversity,CollegeStation,TX77843
*
Towhomcorrespondenceshouldbeaddressed.Email:gwu@tamu.edu.
Copyright2010AmericanSocietyforNutrition

ThisarticlehasbeencitedbyotherarticlesinPMC.

Abstract

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Aminoacids(AA)weretraditionallyclassifiedasnutritionallyessentialornonessentialforanimalsandhumans
basedonnitrogenbalanceorgrowth.AkeyelementofthisclassificationisthatallnonessentialAA(NEAA)were
assumedtobesynthesizedadequatelyinthebodyassubstratestomeettheneedsforproteinsynthesis.
Unfortunately,regulatoryrolesforAAinnutritionandmetabolismhavelongbeenignored.Suchconceptual
limitationswerenotrecognizeduntilrecentseminalfindingsthatdietaryglutamineisnecessaryforintestinal
mucosalintegrityanddietaryarginineisrequiredformaximumneonatalgrowthandembryonicsurvival.Someof
thetraditionallyclassifiedNEAA(e.g.glutamine,glutamate,andarginine)playimportantrolesinregulatinggene
expression,cellsignaling,antioxidativeresponses,andimmunity.Additionally,glutamate,glutamine,andaspartate
aremajormetabolicfuelsforthesmallintestineandthey,alongwithglycine,regulateneurologicalfunction.
AmongessentialAA(EAA),muchemphasishasbeenplacedonleucine(whichactivatesmammaliantargetof
rapamycintostimulateproteinsynthesisandinhibitproteolysis)andtryptophan(whichmodulatesneurologicaland
immunologicalfunctionsthroughmultiplemetabolites,includingserotoninandmelatonin).Agrowingbodyof
literatureleadstoanewconceptoffunctionalAA,whicharedefinedasthoseAAthatregulatekeymetabolic
pathwaystoimprovehealth,survival,growth,development,lactation,andreproductionoforganisms.BothNEAA
andEAAshouldbeconsideredintheclassicidealproteinconceptorformulationofbalanceddietstomaximize
proteinaccretionandoptimizehealthinanimalsandhumans.
Introduction

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Basedongrowthornitrogenbalance(namelynetsynthesisofproteininthewholebody),aminoacids(AA)3have
traditionallybeenclassifiedasnutritionallyessential(indispensable)ornonessential(dispensable)foranimalsand
humans(1,2).NutritionallyessentialAA(EAA)arethosewhosecarbonskeletonsarenotsynthesizedbyanimal
cellsand,therefore,mustbeprovidedfromthediet.DietaryessentialityofsomeAA(e.g.arginine,glycine,proline,
andtaurine)dependsonspeciesanddevelopmentalstage(2).Incontrast,nonessentialAA(NEAA)arethoseAA
thataresynthesizeddenovoinaspeciesdependentmanner(3,4).Itwastacticallyassumed,withoutmuch
evidence,thatanimalsorhumanscouldsynthesizesufficientamountsofallNEAAanddidnotneedthemindiets
foroptimalnutritionorhealth.However,growingevidencefromcellcultureandanimalstudiesshowsthatsomeof
thetraditionallyclassifiedNEAA(e.g.glutamine,glutamate,andarginine)playimportantrolesinmultiple
signalingpathways,therebyregulatinggeneexpression,intracellularproteinturnover,nutrientmetabolism,and
oxidativedefense(57).Additionalworkhasalsoidentifiedthatyoungandgestatingmammalscannotsynthesize
sufficientamountsofallNEAAtosupportmaximumembryonic/fetalsurvival,neonatalgrowth,aswellasvascular
andintestinalhealth(811).Clearly,cellandtissuespecificfunctionsofAAbeyondproteinsynthesis(Fig.1)
shouldbetakenintoconsiderationintherecommendationofnutrientrequirementsforanimalsandhumans.Also,
thelongstandingclassificationofAAasEAAorNEAAhasmajorconceptuallimitationsinproteinnutrition.
Figure1
RolesofAAinnutritionandwholebodyhomeostasis.Besidesservingas
buildingblocksforproteins,AAhavemultipleregulatoryfunctionsincells.
Thesenutrientsarecrucialforgrowth,development,andhealthofanimals
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andhumans.
AgrowingbodyofliteraturehasledtothedevelopmentoftheconceptoffunctionalAA(FAA),whicharedefined
asthoseAAthatregulatekeymetabolicpathwaystoimprovehealth,survival,growth,development,lactation,and
reproductionoforganisms(2).AdeficiencyofaFAA(eitherEAAorNEAA)impairsnotonlyproteinsynthesis
butalsowholebodyhomeostasis.Notably,supplementingaspecificFAA(e.g.glutamineorarginine)toa
conventionaldietthatwastraditionallythoughttoprovideadequateAAcanmaximizegrowthpotentialinyoung
animals(2,12,13)andpreventdiseases(e.g.obesity,diabetes,necrotizingenterocolitis,andintrauterinegrowth
retardation)inbothanimalsandhumans(4).Inviewoftheforegoing,themajorobjectiveofthisarticleisto
highlightrecentadvancesinunderstandingtherolesforFAAinnutrientmetabolism,growth,reproduction,and
health.
Currentstatusofknowledge

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SynthesisofAA

MilkhastraditionallybeenthoughttoprovideadequateamountsofallAAtoneonates.However,resultsofrecent
studieswithlactatingsowsindicatethatmilkprovidesatmostonly40%ofarginineforproteinaccretionin7to
21doldsucklingpigsandthatargininedeficiencyisamajorfactorlimitingtheirmaximumgrowth(13).Besides
arginine,theamountofmilkborneprolinethatenterstheportalveinisinadequatetosupportprolinerequirements
forproteinsynthesisinthepiglet(14).Thus,a7doldpigmustsynthesizedailyatleast0.68garginine/kgbody
weight(13).Basedonadegradationrate[0.93g/(kgbodyweightd)]ofi.v.infusedprolineinyoungpigs,thede
novosynthesisofprolinemustoccuratarateofatleast1.11g/(kgbodyweightd)oratleast60%oftheproline
needforproteinaccretion(14).Additionally,basedonglycineandalaninecontentinsowmilk,milkmeetsatmost
23%and66%,respectively,oftheneedsforproteinsynthesisinpiglets,whichmustsynthesizedailyatleast0.71g
glycineand0.18galanine/kgbodyweight(Table1).Interestingly,althoughaspartateplusasparagineand
glutamateplusglutaminerepresent23and42%,respectively,ofthetotalNEAAinsowmilk(8),thisfoodprovides
atmostonly8and9%ofaspartateandglutamateforproteindepositioninsucklingpigs,respectively.Considering
theextensiveutilizationofarterialglutaminebyenterocytesandothercelltypes(includingkidneysand
lymphocytes)(15),dietaryglutamineisalsosubstantiallyinadequateforproteinsynthesisinextraintestinaltissues
ofpigletsandtherateofdenovosynthesisofglutamineislikelyveryhighinthesucklingpiglet[atleast0.88g/(kg
bodyweightd)].Similarly,atypicalcornandsoybeanmealbaseddietcannotprovidesufficientamountsof
arginine,proline,aspartate,glutamate,glutamine,orglycineforproteinaccretioninpostweaninggrowingpigs(
Table1).
Table1.
UseofdietaryAAforproteinaccretioninsowreared14doldpigsand30
doldpigsweanedat21dofage1
Pathwaysforthesynthesisofarginine,glutamine,glutamate,andprolineandalaninearenowwelldocumentedand
haveimportantnutritionalandphysiologicalsignificance(2,3,14).Incontrast,littleisknownabouthowglycineis
producedinthebody.Althoughbiochemistrytextbooksstatethatglycineissynthesizedfromserine,81%ofmilk
bornserineisutilizedforproteindepositionandthedietprovidesatmost0.32gofserineforglycineformationin
youngpigs(14).Therefore,90%ofglycinemustbesynthesizedfromprecursorsotherthanserine.Currently,the
underlyingpathways(includingsubstratesandreactions)forglycinesynthesisarelargelyunknown.These
pathwaysareexpectedtobenutritionallyandphysiologicallyimportant,becausehighratesofglycineutilization
supportthesynthesisofprotein,creatine,N5N10methylenetetrahydrofolate,nucleotides,andothernitrogenous
products(2,16).CatabolismofEAAisnecessaryforthesynthesisofNEAAinacellandtissuespecificmanner(
Fig.2).
Figure2
CatabolismofnutritionallyEAAforthesynthesisofAAinanimals.Dietary
intakeofmostEAAexceedstheiruseforproteinsynthesisinthebody.In
contrast,thetypicalcornandsoybeanmealbaseddietcannotprovide
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sufficientamountsofarginine,...
DegradationofAA

Ithadbeenalongstandingbeliefthatafterdigestion,dietaryAAabsorbedbyenterocytesenteredtheportalvein
intact.However,thisconcepthasrecentlybeenchallengedbyfindingsfromstudieswithyoungpigsthatboth
EAAandNEAAintheenteraldietaredegradedextensivelybythesmallintestineinfirstpass,with<20%ofthe
extractedAAbeingutilizedforintestinalmucosalproteinsynthesis(17).Nearlyallofglutamateandaspartate,67
70%ofglutamine,and3040%ofprolineintheenteraldietarecatabolizedbythesmallintestineofneonatal,
weaned,andgestatingswine(14).Thus,only5%ofglutamateandaspartate,3033%ofglutamine,and6065%
ofprolineinthedietentertheportalcirculation.Inpostweaningpigsandhumans,40%ofdietaryarginineis
catabolizedbythesmallintestineinthefirstpass(4).AmongdietaryAA,therateofdegradationinthesmall
intestineisthegreatestforglutamate,followedbyglutamine,aspartate,andproline.Ofparticularnote,thesmall
intestinetakesupalargeamountofglutamine,butnoglutamateoraspartate,fromthearterialblood.Consequently,
thetotalrateofutilizationofglutaminebythegutmaybegreaterthanthatforglutamate.Bacteriaintheintestinal
lumencandegradeEAAandNEAA(18,19),butEAAoxidationinenterocytesislimited(20,21).Nitrogenous
productsofglutamateandglutamineincludeornithine,citrulline,arginine,proline,aspartate,andalanine(2).
Despitemuchworkonglutamateoxidationinthegut,littleisknownabouttheeffectsofdietaryglutamate
supplementationonintestinalmucosalintegrityandfunction,particularlyunderstressfulconditions.
IntestinalmetabolismofAAhasprofoundimpactsonnutritionandhealth.First,catabolismofglutamine,
glutamate,andaspartateprovidesmostoftheATPtomaintaingutintegrityandfunction(3).Second,because
elevatedlevelsofglutamine,glutamate,andaspartateinplasmaexertaneurotoxiceffect(2),theirextensive
catabolismbythesmallintestineisessentialtothesurvivaloforganisms.Third,transformationsofAAinthe
intestineplayanimportantroleinregulatingendogenoussynthesisofNEAA(e.g.citrulline,arginine,proline,and
alanine)andmodulatingtheavailabilityofdietaryAAtoextraintestinaltissues(18).Thus,theratiosofmostAAin
dietsrelativetolysinediffermarkedlyfromthoseenteringtheportalveinfromthesmallintestinallumenor
appearinginplasmaandbodyproteins(14).ThediscrepanciesinthepatternsofAAbetweendietsandbody
proteinsareparticularlylargeforarginine,histidine,methionine,proline,glutamine,glycine,andserine(14).
Therefore,ratiosoftheseAAtolysineinbodyproteinsarenotaccurateestimatesoftheiroptimaldietary
requirementsbyrapidlygrowinganimalsorinfants.Thisconceptuallimitationalsoappliestogestatingand
lactatingdams.TheclassicconceptofidealproteinmustbemodifiedtoincludeallNEAA.
RegulatoryroleforAAingeneexpressionandproteinturnover

RegulatoryeffectsofcertainAAongeneexpressionmaybemediatedbytranscriptionfactors(includingthebasic
region/leucinezipperfactors,activatingtranscriptionfactors,andCCAAT/enhancerbindingprotein),specific
regulatorysequences(includingAAresponseelements,nutrientsensingresponseelements,andmultiplesites)in
thepromoter,andvariousciselementsdistinctfromAAresponseelementsornutrientsensingresponseelements
(5,6).TwoofthemoststudiedAAregardingregulationofgeneexpressionareglutamineandarginine.For
example,dietaryglutaminesupplementationincreasedintestinalexpression(120124%)ofgenesthatarenecessary
forcellgrowthandremovalofoxidants,whilereducing(3475%)expressionofgenesthatpromoteoxidative
stressandimmuneactivation(22).Thesefindingsprovidemolecularmechanismsforthebeneficialeffectsof
dietaryglutaminesupplementationtoimprovenutritionalstatusinyoungmammals.Also,dietaryarginine
supplementationreducedmRNAlevelsforfattyacidbindingprotein1,glycogenin,proteinphosphotase1B,
caspases1and2,andhepaticlipase,butincreasedexpressionofPPAR,hemeoxygenase3,glutathione
synthetase,insulinlikegrowthfactorII,sphingosine1phosphatereceptor,AMPactivatedproteinkinase(AMPK),
andstressinducedproteininwhiteadiposetissue(WAT)ofdietinducedobeserats(23).IntheadultratWAT,
thereisnosynthesisoffattyacidsduetothelackofacetylCoAcarboxylase,butarginineenhanceslipolysisinthis
tissue(2325).Therefore,enhancedexpressionofPPARdoesnotcontributetoadipogenesisinadultobeserats.
BiochemicalanalysishasrevealedthatoxidativestressintheobeseratWATcanbepreventedbyarginine
supplementation(24).Also,upregulationofgenesinvolvedinmitochondrialbiogenesisbyarginineprovides
anothermechanismforincreasedoxidationoflongchainfattyacidsandglucoseininsulinsensitivetissues(25).
Histonemodificationsbymethylation,acetylation,andphosphorylation,aswellasDNAmethylation(occurringin
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the5positionsofcytosineresidueswithinCpGdinucleotidesthroughoutthemammaliangenome)playan
importantroleinepigeneticregulationofgeneexpressionandphysiologicalfunctions(26).AA(e.g.methionine,
histidine,serine,andglycine)aremajordonorsof1carbongroupsthatmayaffecttheseeventsandrelated
reactions,includingactivitiesofhistoneacetyltransferase(e.g.cAMPresponseelementbindingprotein)and
acetylase,aswellasspecificDNAmethyltransferases(27).Uponacetylationofhistones,DNAisdissociatedfrom
histonessothattranscriptionwillproceed.Incontrast,DNAmethylationandhistonedeacetylationresultinhighly
densepackingofDNAand,therefore,silencegeneexpression.
RNApolymerasecatalyzesthetranscriptionofagenetomRNA.ThisprocesscanberegulatedbyAAthrough1
ormoreofthefollowingmechanisms:1)alterationofspecificityofRNApolymeraseforpromoters2)bindingof
repressorstononcodingDNAsequencesthatarenearoroverlapthepromoterregionand3)transcriptionfactors
(e.g.upregulation,downregulation,coactivators,andcorepressors)(27).Posttranscriptionalregulationismediated
bycapping(changingthe5endofthemRNAtoa3end,conferringprotectionofthemRNAfrom5
exonuclease),splicing(removingintronsandjoiningofexons),andtheadditionofapoly(A)tail(polyadenylation)
toconferprotectionofmRNAfrom3exonuclease(2).CovalentmodificationsofDNAandcorehistonesprovide
abasisforepigenetics(stablealterationsingeneexpressionwithoutchangesintheunderlyingDNAsequence)(26,
28).Epigeneticchangesmayremainthroughcelldivisionsand,therefore,maybecarriedforwardtosubsequent
generations(28).ThisnotionoftransgenerationaleffectsofAAhasimportantimplicationsforhumanhealthand
animalproduction.
InitiationofmRNAtranslationisakeyeventintheregulationofproteinsynthesis.Themammaliantargetof
rapamycin(mTOR),ahighlyconservedserine/threonineproteinkinase,isthemasterregulatorofmRNA
translation(29)mTORisalsoknownasFK506bindingprotein12rapamycinassociatedprotein1.ThemTOR
systemconsistsofmTORcomplex1(mTOR,raptor,andGproteinsubunitlikeprotein)andmTORcomplex2
(mTOR,rictor,mitogenactivatedproteinkinaseassociatedprotein1,andGproteinsubunitlikeprotein)(30).
mTORcomplex1issensitivetoinhibitionbyrapamycin.AA(e.g.glutamine,arginine,andleucine)stimulatethe
phosphorylationofmTORinacellspecificmanner,leadingtophosphorylationofribosomalproteinS6kinase1
andeukaryotictranslationinitiationfactor4Ebindingprotein1and,therefore,theformationoftranslationinitiation
complex(7,31,32).ActivationofmTORmayalsoresultininhibitionofintracellularproteindegradation,possibly
viamechanismsinvolvingautophagyandotherunknownpathways(2,32).Inadequatecontentofarginineand
glutamineaswellasotherNEAAinalowprotein(12.7%crudeprotein)dietmayexplainwhydietary
supplementationwithdeficientEAA(lysine,methionine,threonine,tryptophan,leucine,isoleucine,andvaline)
wasineffectiveinrestoringproteinsynthesisorwholebodygrowthinweanlingpiglets(33).
TherearesuggestionsthatsomeAAmaydirectlyacttophosphorylatemTORoritsdownstreamtargetproteins
(25,34).EvidencealsoexiststhatcertainAAmayindirectlydosoviatheproductionoftheirmetabolites(35)or
interactionwithRagGTPasesforbindingraptor(36).Althoughresultsfromcellculturestudiesledto3modelsto
explainhowAAcanregulateproteinsynthesisincells(Fig.3),thephysiologicalrelevanceofthesemodels
remainstobeestablished.Thisisbecauseinvitroexperimentswereconductedunderconditionsofeithercomplete
absenceofanAAoritspresenceataparticularlyhighconcentration(e.g.2mmol/Latleast10timestheplasma
concentrationsformostAA)inculturemedium(37,38).Nonetheless,thepotentialforFAA(eitherEAAor
NEAA)tostimulateproteinsynthesisindicatesthatthesenutrientsplayimportantregulatoryrolesbeyondserving
asbuildingblocksofproteins.
Figure3
ModelsforregulatoryrolesofAAinproteinsynthesis.Provisionof
sufficientamountsofAApromotesthebindingofGTPtoRagGTPase
leadingtomTORC1activation,whilereducingconcentrationsofuncharged
tRNAandactivityoftheGCN2independent...
RolesofAAingaseoussignaling

SomeAA(e.g.arginineandglutamine)modulatecellularsignalinginvolvingAMPK,extracellularsignalrelated
kinase,Junkinase,andmitogenactivatedproteinkinase(39).EmergingevidenceshowsthatNO,CO,andH2S
arephysiologicallyimportantsignalinggases(40).NO,CO,andH2SaresynthesizedfromL arginine,L cysteine,
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andglycine(heme),respectively.ManyAAhavebeenreportedtoregulatetheproductionofNO,CO,andH2Sin
acelldependentmanner(40,41).Forexample,arginine,citrulline,glutamate,glycine,taurine,and
aminobutyrateincreaseNOsynthesisbyconstitutiveNOsynthaseinendothelialcellsorbrain,whereaslowprotein
intake,glucosamine,glutamine,andlysineinhibitNOgenerationbybothconstitutiveandinducibleNOsynthases
(41).Inaddition,highproteinintake,arginine,glutamine,glutamate,alanine,taurine,methionine,andglycine
promoteCOsynthesisbyhemeoxygenaseinendothelialcellsandnonvasculartissues,butNacetylcysteine
attenuatesCOformationininjuredbrainandvascularsmoothmusclecells(40).Furthermore,H2Sproductionis
stimulatedbyhighproteinintake,arginine,cysteine,methionine,glycine,Sadenosylmethionine,Nacetyl
glutamate,andglutamate(0.1mmol/L)butisinhibitedbyaspartateandhigherlevelsofglutamate(13mmol/L)in
variouscelltypes(40).EitherimbalanceorantagonismamongAAaffectsthegenerationof1ormoreofthese
gaseousmoleculesand,therefore,proteinnutritioninorganisms.
NOisahighlyreactivefreeradical(41).Incontrast,CO,H2S,andSO2arestrongreducingagents.Theyareall
watersoluble,colorlessmoleculesthateasilypenetratebiologicalmembranes.Therefore,thesegasesexerttheir
effectsoncellsindependentofmembranereceptors.Becauseoftheirchemicalproperties,theeffectsofNO,CO,
H2S,andSO2dependontheirrespectiveconcentrationsincells.Atpathologicallevels,theyareextremely
destructivetoallcelltypes(40,41).Atphysiologicallevels,NO,CO,andSO2activateguanylylcyclaseto
generatecGMP,whichelicitsavarietyofresponsesviacGMPdependentproteinkinasesthatincluderelaxationof
vascularsmoothmusclecells,hemodynamics,neurotransmission,andcellmetabolism(40,42).Theactionsof
thesegasesmayalsoinvolvecGMPindependentmechanisms(e.g.inhibitionofornithinedecarboxylase,protein
modification,andredoxstate).EmergingevidenceshowsthatH2Sisacrucialregulatorofbothneurological
functionandendotheliumdependentrelaxationthroughcGMPindependentmechanismsinvolvingstimulationof
membraneKATPchannelsandintracellularcAMPsignaling(43).Moreover,physiologicallevelsofNO,CO,and
H2Sconfercytoprotectiveandimmunomodulatoryeffects.
Translationalresearchbenefitinghumanhealthandanimalproduction

AAareessentialprecursorsforthesynthesisofawidearrayofnitrogenoussubstanceswithenormousbiological
importance(2).Someofthesebioactivemoleculesincludeneurotransmitters(e.g.aminobutyrate,dopamine,and
serotonin),hormones(e.g.epinephrine,norepinephrine,triiodothyronine,andthyroxine),vasodilators,signaling
gases(NO,CO,andH2S),antioxidants(glutathione,creatine,melatonin,melanin,andtaurine),methylgroup
donors,aswellaskeyregulatorsofmetabolism,growth,development,immuneresponse,andhealth.Metabolism
ofAAisalteredundervariousphysiologicalandpathologicalconditions,leadingtochangesinwholebody
homeostasis(14,16,44,45).
Historically,ourunderstandingofhumanproteinnutritionhasbeenbasedlargelyonanimalstudies(13).The
relativegrowthrates(percentchangeperday)andfoodintake(percentofbodyweight)ofrodents,pigs,and
poultryarehigherthanthoseforhumansandprimates(4650).BecausethecompositionofAAinthebodyis
similaramongspecies(2),requirementsofintracellularAA(e.g.relativeproportionsofAA)forproteinsynthesis
arenotexpectedtovarysubstantially.Thus,newknowledgegainedfromanimalmodelshasimportantimplications
forhumannutrition.First,asreportedforsowrearedpiglets(8),provisionofargininefromhumanorprimatemilk
isinadequateforoptimalproteinaccretioninbreastfedinfants(46).Thisnecessitatesendogenoussynthesisof
argininefromglutamate,glutamine,andprolineininfants(4).Second,dietarysupplementationwitharginine
preventsnecrotizingenterocolitis(themostcommonandsevereintestinaldisease)inpreterminfants(47),whohave
underdevelopedargininesyntheticenzymesandinsufficientarginineintake(48).Similarly,arginineameliorates
intestinaldamageinearlyweanedpigletswithnaturallyoccurringgutatrophy(12).Third,adeficiencyofdietary
glutamineimpairscellsignalingandresultsinintestinalatrophyinbothpigletsandinfants(39).
BecauseofspeciesdifferencesinabsoluterequirementsofdietaryAA[expressedasg/(kgbodyweightd)],
cautionsshouldbetakentoextrapolateanimaldatatohumans.Nonetheless,newknowledgeaboutAA
biochemistryandphysiologyhasresultedinfruitfultranslationalresearchtoimprovehumanandanimalhealth,as
wellasanimalproduction.Forexample,supplementationwithAA(e.g.glutamine,arginine,andNacetylcysteine)
improvesoxidativedefense(51)andimmunefunction(41)inbothhumansandanimals.Studieswithpigs,sheep,
andratshavealsodemonstratedthatglutamineandarginineenhancethesurvival,growth,anddevelopmentofthe
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embryo,fetus,andneonate(4,14)aswellasintestinalrestitution,integrity,andfunction(39).Additionally,
arginineamelioratesobesity,hyperglycemia,dyslipidemia,hypertension,cardiovasculardysfunction,andother
problemsofmetabolicsyndromeinhumansandanimalswhileenhancingmilkproduction,mitochondrial
biogenesis,growthofbrownadiposetissue,woundhealing,muscularstrengthandglycolysis,andspermatogenesis
(4,9,14,52).Meatqualitycanalsobeimprovedthroughsupplementingargininetogrowingfinishingpigsbefore
slaughter(53,54).Furthermore,prolinesupplementationstimulatessmallintestinalandwholebodygrowthin
weanlingpigs(10).Collectively,thesefindingsnotonlygreatlyadvanceourknowledgeofFAAbutalso
exemplifythepowerofbasicresearchinsolvingpracticalproblemsinbothhumanhealthandanimalproduction.
Perspectives

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ThereisadynamicequilibriumbetweenfreeAAandproteinboundAAinthebody(2).Concentrationsoffree
individualAAinplasmaandcellsrangefrom0.01to1and0.05to20mmol/L,respectively,dependingonspecies,
developmentalstage,andcelltype(24,49).Itshouldbeborneinmindthatphysiologicalsignificanceand
functionaleffectsofbiochemicalsubstancesarenotnecessarilyreflectedbytheirconcentrations.Forexample,
hepaticconcentrationsofarginineinmammalsaregenerally<0.1mmol/Lbutplayanessentialroleinammonia
detoxificationviatheureacycle(4).Additionally,althoughconcentrationsoftryptophanaremuchlowerthan
concentrationsofvalineinallcelltypes,tryptophanhasmoreversatilerolesthanvalineinthebody(2).
Itremainsasubjectofphilosophicaldebatewhetherornotmaximizingproteinaccretioninhumansisdesirablefor
healthandlongevity.However,maximumdepositionofdietaryAAasbodyproteinsshouldbeachievedfor
childrenwhoexperiencegrowthretardationduetoinadequateintakeofproteinordisease.Althoughhumanseat
foodsbutnotformulateddiets,provisionofAAinproperratiosiscrucialforgastrointestinal,cardiovascular,and
reproductivehealth(49,50).ItshouldalsoberecognizedthatnotallNEAAcarbonsinthebodyarederivedfrom
dietarysourcesaspyruvate,oxaloacetate,andalphaketoglutaratecanbesynthesizedfromendogenousglucose.
Indeed,datapresentedinTable1clearlyindicatethatlargeamountsofNEAAareformedfromEAAingrowing
pigs(Fig.1).Thisisalsotrueforglutamate,aspartate,andglutamineininfantsandadulthumans(15).
ThetraditionalclassificationofAAasnutritionallyessentialornonessentialhasmajorconceptuallimitationsin
proteinnutrition.ItisunfortunatethatthecurrentversionsofNRCorInstituteofMedicinebooksdonot
recommenddietaryrequirementsofNEAAforanimalsorhumans(55,56).However,emergingevidenceshows
thattraditionallyclassifiedNEAA,particularlyglutamineandarginine,playimportantrolesinregulatinggene
expressionatbothtranscriptionalandtranslationallevels(57,58).ThereisgrowingrecognitionthatsomeNEAA
participateincellsignalingviamTOR,AMPK,extracellularsignalrelatedkinase,Junkinase,mitogenactivated
proteinkinase,andgases(NO,CO,andH2S)(39,43).Exquisiteintegrationoftheseregulatorynetworkshas
profoundeffectsoncellproliferation,differentiation,metabolism,homeostasis,survival,andfunction.Among
EAA,muchemphasishasbeenplacedonleucine(whichactivatesmTORtostimulateproteinsynthesisandinhibit
proteolysis)andtryptophan(whichmodulatesneurologicalandimmunologicalfunctionsthroughmultiple
metabolitesincludingserotoninandmelatonin)(5961).BecausedietaryAAaresubstantiallycatabolizedbythe
smallintestine,ratiosofAAinthedietdiffermarkedlyfromthoseinskeletalmuscleorthebody(2).Thus,the
classicconceptoftheidealprotein,whichisbasedsolelyonratiosofEAAintissueproteins(1),shouldbe
revisedtoincludeallNEAA.Inotherwords,bothEAAandNEAAshouldbetakenintoconsiderationin:1)
formulationofbalanceddietstomaximizegrowthperformanceinlivestockspecies,poultry,andfish2)
recommendationofAArequirementsforhumanstopreventgrowthretardationandchronicdiseasesand3)
optimizationofimmuneandreproductivefunctionsinallspecies.Unquestionably,recentadvancesin
understandingFAAareexpandingourbasicknowledgeofproteinmetabolismandtransformingthepracticesof
nutritionworldwide.Nutritionistsmustthinkoutoftheboxandmoveforwardtocapitalizeonthegreatpotentialof
FAAinimprovingbothhumanhealthandanimalproduction.
Acknowledgments

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Contributionsofcolleaguesandstudentstotherecentdevelopmentofthefieldaregratefullyappreciated.G.W.
wrotethepaperandhadsoleresponsibilityforitsfinalcontent.
Footnotes
1

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1SupportedbyNationalResearchInitiativeCompetitivegrantsfromtheAnimalReproductionProgram(20083520319120)and
AnimalGrowthandNutrientUtilizationProgram(20083520618764)oftheUSDANationalInstituteofFoodandAgriculture,
NIH(1R21HD049449),AHA(10GRNT4480020),andTexasAgriLifeResearch(H8200).
2Authordisclosure:G.Wu,noconflictsofinterest.
3
Abbreviationsused:AA,aminoacidAMPK,AMPactivatedproteinkinaseEAA,nutritionallyessentialaminoacidFAA,
functionalaminoacidmTOR,mammaliantargetofrapamycinNEAA,nutritionallynonessentialaminoacidWAT,white
adiposetissue.

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