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ProteinsandAlbumin
RogerL.Bertholf,PhD,DABCC,FACB
LabMed.201445(1):e25e41.

Abstract
Proteinsarelargepolymersofaminoacidslinkedbypeptidebonds(Figure1).Theaminoacid
subunitsofproteinsareorganicmoleculesthatincludeacarboxylicacidlinkedthroughacarbonatomtoaprimary(orsecondary,
inproline)aminewiththechemicalformulaH2NCHRCOOH,inwhichRisasidegroupthatlargelydeterminesthechemical
propertiesoftheaminoacid.Thesimplestaminoacidisglycine,H2NCH2COOH,inwhichtheRsidegroupisahydrogenatom.
AlthoughthischemicaltemplatecanbemodifiedintoaninfinitearrayofmoleculesbasedonvariationsintheRgroup,only
approximately20aminoacidsoccurinproteins.TheRgroupsconferacidic,alkaline,polar,ornonpolarpropertiestothevarious
aminoacids.

Figure1.

Thepeptidebond(oramidebond)isformedwhenaprimaryaminereactswithacarboxylicacid.BecauseamoleculeofH2Ois
lostinthereaction,thereactionconstitutesdehydrationsynthesis,whichcanbereversedbyhydrolyticcleavage.However,the
reversereactionisveryslowasaresult,peptidebondsarestableatphysiologicaltemperaturesandpH.Digestionand
metabolismofproteins(proteolysis)arecatalyzedbyproteaseenzymes.

StructureandNomenclature
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overload
Ferritin

Tissueironstorageprotein

Correlateswithtotalbodyironlevelsalso,anacutephase
reactant

Creactive
protein(CRP)

Homopentamericproteinproducedintheliver

Increasesinresponsetoinflammationriskfactorfor
cardiovasculardisease

TroponinIand
troponinT

Inhibitory(I)andtropomyosinbinding(T)
subunitsoftheactinmyosincomplexin
muscle

Cardiacspecificformsoftroponinarereleasedintothe
circulationwhenmyocytesaredamagedbyischemiaand
infarction

Elevatedinbenignprostatichypertrophyandprostate
Prostatespecific ProteaseglycoproteinintheKallikreinfamily,
cancerusedasascreeningtestforprostatecancerand
antigen(PSA)
producedintheprostategland
tomonitortherapeuticregimen
Myoglobin

Releasedintothebloodstreamwhenmuscleisdamaged
Oxygenbindingproteininmuscle,analogous
fromtraumaordisease(eg,musculardystrophy,
tohemoglobin
rhabdomyolysis)

Haptoglobin

Hemoglobinbindingprotein

Increaseinhemolyticdisease

1antitrypsin

Proteaseinhibitor

Geneticdeficiencyassociatedwithemphysema

CA125,CA19
9,CA125,etc

Carbohydrateantigen(CA)glycoproteins,
Elevationsareassociatedwithcertaintumorsnoneare
sometimescalledmucins,thatareexpressed entirelyspecifichowever,thesemarkersareusefulin
byepithelialtissue
monitoringtumorrecurrenceaftertherapeutictreatment

Fetoprotein

Thoughttobeafetalformofalbumin

Associatedwithfetalabnormalitiesandsometimes
observedingermcelltumors

Fibrinogen

Convertedbythrombintofibrinduringclot
formationthethirdmostabundantproteinin
serumafteralbuminandimmunoglobulins

Depletedinhypercoagulationdisorders

Heavychainclassesimmunoglobulin(Ig)G,
Immunoglobulins IgM,IgA,IgEsecondmostabundant
proteinsinserumafteralbumin

Decreasedinimmunodeficiencydiseasesandincreasedin
manydiseases

C3andC4
complement
proteins

Proteinsnecessaryforproperfunctionofthe
complementsystem

Abnormalitiesincomplementproteinsareassociatedwith
avarietyofimmunesystemdisorders

Lipoproteins

Proteinsassociatedwithlipidtransportin
blood

Highconcentrationsoflipoproteins(specifically,low
densitylipoprotein[LDL]cholesterol)areassociatedwith
riskofcardiovasculardisease

SerumAlbumin

Inadditiontobeingthemostabundantproteininserum(3.55.0g/dL,whichconstitutesapproximatelyhalfofallserum
proteins),albuminhasseveralimportantcharacteristics.Itisananionicprotein,containinganabundanceofaspartateand
glutamateresiduesitisnotfunctionallymodifiedwithcarbohydrates 12amongallserumproteins,ithasamidrangemolecular
weight(67kDa)andithasalongerthanaveragehalflifeofapproximately20days.Albuminhelpsmaintainosmoticbalance
betweenintravascularandinterstitialspacestherefore,adeficiencyinalbuminordinarilyresultsinedemaaswateris
redistributedtotissues.Albuminalsofunctionsasatransportproteinforcalcium(approximatelyhalfofcirculatingcalciumions
areboundtoalbumin),unconjugatedbilirubin(whichcanbecovalentlyornoncovalentlyboundtoalbumin),thyroidhormones
(approximately20%ofT4and10%ofT3isboundtoalbumin),andmanydrugs.
Becausealbuminhasalongerhalfliferelativetomanyotherproteins,itsconcentrationinserumisapoorindicatorofnutritional
deficiencyorimpairedsynthesisprealbuminproteinsandcoagulationfactorsaremoresensitivemeasuresofimpairedprotein
synthesisbecausetheirhalflivesaremuchshorter.Thereasonfordecreasedserumalbuminisusuallyrenalloss.Glomerular
membranepermeabilityispartiallyafunctionofsizebutalsoisrelatedtochargethenegativechargeonalbumininhibitsits
filtrationbecausethemembranelikewiseisnegativelycharged.Diseasesthatcausedamagetotheglomerularmembrane
increaseitspermeabilitytoallproteinshowever,itspermeabilitytoalbuminmaybeparticularlyaffectedifthenegatively
chargedgroupsonthemembranesurfaceareneutralized.Thisappearstobetheprincipalmechanismofalbuminuriaassociated
withdiabeticnephropathy.
Althoughalbuminishighlyconservedacrossmanyspecies,thereexistmostlybenignpolymorphismsinthegenesthatcodefor
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thisprotein.Forexample,thereareformsofalbuminthathavehigherthannormalaffinityforthyroidhormonesthesedonot
produceclinicalmanifestationsbutmaycauseerrorsinimmunochemicalmethodsthatmeasurefreehormoneconcentrations
becausethemethodsarebasedoncompetitionbetweenantibodiesagainstthyroidhormonesandendogenoushormonebinding
proteins.AlbuminwithincreasedaffinityforthyroxinewillalsoresultinelevatedtotalT4concentrationsinpatientswithhealthy
thyroidglandfunctionbecauseonlythefreefractionofthyroidhormonesisbiologicallyactive.Anotheralbuminvariantresultsin
bisalbuminemia,abenigndisorderinwhich2distinctalbuminpeaksappearonanSPEgel.
Afascinatingparadoxsurroundsalbumin:itisaproteinthatishighlyconservedacrossmanyspeciesandhasuniqueproperties
thatseemfunctionallyindispensable,suchasbufferingtheserumionizedcalciumconcentration,osmoregulationofplasma
volume,solubilizingunconjugatedbilirubin,andbindingcationicdrugs.Thelogicofevolutionarydesignwouldarguethatsucha
proteinmustbeessentialforlife. 13However,anextremelyrareautosomalrecessivegeneticdefectimpairsalbuminsynthesis
andproducesanalbuminemia,ortheabsenceofalbuminintheblood.Thisconditionisbenignitproducesonlymildedema.
Elevationsinserumalbuminareuncommonandnotclinicallysignificant.
UrineProteins

Mostcirculatingproteinsareconservedinthekidneysbyexclusionfromtheglomerularfiltrateorreabsorptionfromtherenal
tubulesfailureofeithermechanismcausesexcessproteinlevelsintheurine.Proteinuriamayalsooccurwhenrenalfunctionis
adequateiftheconcentrationofacirculatingproteinissohighthatfiltrationandreabsorptionmechanismsareoverwhelmed
(overflowproteinuria).Finally,proteinsecretedbytherenaltubularepitheliumappearsintheurine(TammHorsfallproteinalso
knownasuromodulin)however,itsclinicalsignificanceisnotwellestablished. 14Minuteamountsofsomeserumproteins
normallyappearintheurine,includingalbumin(<100mg/d)andcertainenzymessuchasCKandamylaseproteinuriarefersto
amountsthatexceedtheamountofnaturallyexcretedproteins.Thevaryingdegreesofseverityofproteinuriaandtheirmost
commoncausesaresummarizedin.
Table6.ClassificationandCausesofProteinuria

Classification Proteinuria Causes

Minimal

<1g/d

Chronicpyelonephritis,mildglomerulardisease,nephrosclerosis(usuallyduetohypertension),
chronicinterstitialnephritis(usuallyanalgesicrelated),andrenaltubulardisease

Moderate

14g/d

Usuallyassociatedwithglomerulardiseasealso,overflowproteinuriafrommultiplemyeloma
andtoxicnephropathicmanifestations

Severe

>4g/d

Nephroticsyndromeinadults,usuallysecondarytosystemicdisease(lupus,diabetes)in
children,usuallyprimaryrenaldiseaseminimalchangeindisease(lipoidnephrosismost
commoninchildren)

Themethodscommonlyusedtomeasureurineproteinsareurinetotalproteinmeasuredviathebiuretmethod,urinealbumin
measuredviabromocresolgreenorpurplemethods,andIFEusedtoidentifyimmunoglobulinlightchainsinurine.Theurine
dipstickmethodformeasuringproteininurineinvolvesdyethatproducesachangeinpHinthepresenceofprotein.Becausethe
dyeismostreactivewithalbumin,dipstickurineproteinmethodsarepoorindicatorsofoverflowandtubularproteinurias.
Themostcommoncauseofproteinuriaisnephroticsyndrome(NS),anonspecifictermthatreferstoincreasedpermeabilityof
theglomerularmembrane.NStypicallyresultsfromglomerulonephritis,orinflammationoftheglomeruli.Glomerulonephritismay
occurbecausethediseaseaffectsonlythekidney(primaryglomerulonephritis)oritmayresultfromsystemicillness(secondary
glomerulonephritis)thelatterismorecommon.Clinically,NSischaracterizedbyproteinuria(usually>3.5g/d)hypoalbuminemia
(becausealbuministhemostabundantproteininblood,itslossinNSismostpronounced)edemaduetolossofalbumin
regulatedmaintenanceofintravascularosmolalityandhyperlipidemia,thecausesofwhicharemultifactorial.Inchildrenaged1
to7years,approximately90%ofNScasesarecausedbyminimalchangedisease(lipoidnephrosis),theetiologyofwhichhas
notbeenestablished.Inadults,NSisusuallytheresultofsecondaryglomerulonephritisduemostoftentodiabetesorlupus.
Milderproteinuriacanhavemanycauses,includingpyelonephritis,drugtoxicity,nephrosclerosis(usuallyduetohypertension),
andoverflowproteinuria.
Overflowproteinuriaismostoftencausedbyoverproductionofimmunoglobulinsinmultiplemyeloma(MM).MostcasesofMM
produceimmunoglobulinG,althoughclonalproliferationofalltheotherheavychainimmunoglobulinisotypes(IgA,IgE,IgM,
andIgD)havebeenobservedinthedisease.InMM,theplasmacellsexpressnotonlyintactimmunoglobulinsbutalsofree
heavyandlight(and)chainfragments.Igheavychainsareapproximately50kDainsize,whereaslightchainsare
approximately25kDaintactIgGisusually150kDa.Becauseoftheirsmallsize,lightchainscancrosstheglomerular
membranewhentheirconcentrationishighenough,theycanoverwhelmthereabsorptivecapacityofrenaltubules.Thus,
immunoglobulinlightchainsappearintheurineinMM,andcollectivelyarecalledBenceJonesprotein.UrineIFEtestingcan
confirmthemonoclonalityofagammopathicentitywhenasinglespotappearsinthekappaorgammastainedlaneofthegel.
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