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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
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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