Plasma proteins

Biochemistry For Medics
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Biochemistry For Medics 7/11/2012 1

Plasma consists of water, electrolytes,
metabolites, nutrients, proteins, and hormones.
The concentration of total protein in human
plasma is approximately 6.0–8.0 g/dL and
comprises the major part of the solids of the
plasma.
The proteins of the plasma are a complex
mixture that includes not only simple proteins
but also conjugated proteins such as
glycoproteins and various types of lipoproteins.


Salting-out methods-three major groups—
fibrinogen, albumin, and globulins—by the
use of varying concentrations of sodium or
ammonium sulfate.
Electrophoresis- five major fractions
Albumin
α1 and α2 globulins
β globulins

 γ globulins


Albumin (69 kDa) is the major protein of
human plasma (3.4–4.7 g/dL)
Makes up approximately 60% of the total
plasma protein.
About 40% of albumin is present in the
plasma, and the other 60% is present in the
extracellular space.
Half life of albumin is about 20 days.
Migrates fastest in electrophoresis at
alkaline pH and precipitates last in salting
out methods


The liver produces about 12 g of albumin
per day, representing about 25% of total
hepatic protein synthesis and half its
secreted protein.
Albumin is initially synthesized as a
preproprotein
Its signal peptide is removed as it passes
into the cisternae of the rough endoplasmic
reticulum, and a hexapeptide at the resulting
amino terminal is subsequently cleaved off
farther along the secretory pathway.

Mature human albumin consists of one
polypeptide chain of 585 amino acids and
contains 17 disulfide bonds
It has an ellipsoidal shape, which means
that it does not increase the viscosity of the
plasma as much as an elongated molecule
such as fibrinogen does.
Has a relatively low molecular mass about
69 kDa
Has an iso-electric pH of 4.7


 Colloidal osmotic Pressure-albumin is
responsible for 75–80% of the osmotic
pressure of human plasma due to its low
molecular weight and large concentration
It plays a predominant role in maintaining
blood volume and body fluid distribution.
Hypoalbuminemia leads to retention of fluid
in the tissue spaces(Edema)


Transport function-albumin has an ability to
bind various ligands, thus acts as a
transporter for various molecules. These
include-
 free fatty acids (FFA),
calcium,
certain steroid hormones,
bilirubin,
copper
A variety of drugs, including sulfonamides,
penicillin G, dicoumarol, phenytoin and
aspirin, are also bound to albumin

Nutritive Function
Albumin serves as a source of amino acids for
tissue protein synthesis to a limited extent,
particularly in nutritional deprivation of amino
acids.
 Buffering Function-Among the plasma
proteins, albumin has the maximum buffering
capacity due to its high concentration and the
presence of large number of histidine residues,
which contribute maximally towards
maintenance of acid base balance.
Viscosity- Exerts low viscosity


Blood brain barrier- Albumin- free fatty
acid complex can not cross the blood brain
barrier, hence fatty acids can not be utilized
by the brain.
Loosely bound bilirubin to albumin can be
easily replaced by drugs like aspirin
In new born if such drugs are given, the
released bilirubin gets deposited in brain
causing Kernicterus.


Protein bound calcium
 Calcium level is lowered in conditions of
Hypo- Albuminemia
 Serum total calcium may be decreased
 Ionic calcium remains same
Tetany does not occur
Calcium is lowered by 0.8 mg/dl for a fall of
1g/dl of albumin


Drug interactions—
Two drugs having same affinity for albumin
when administered together, can compete for
available binding sites with consequent
displacement of other drug, resulting in
clinically significant drug interactions.
Example-Phenytoin, dicoumarol interactions


Edema- Hypoalbuminemia results in fluid
retention in the tissue spaces
Normal level- 3.5-5 G/dl
Hypoalbuminemia- lowered level is seen in the
following conditions-
Cirrhosis of liver
Malnutrition
Nephrotic syndrome
Burns
Malabsorption
Analbuminemia- congenital disorder
Hyperalbuminemia- In conditions of fluid
depletion(Haemoconcentration)


Globulins are separated by half saturation
with ammonium sulphate
Molecular weight ranges from 90,000 to
13,00,000
By electrophoresis globulins can be
separated in to –
α1-globulins
α2-globulins
β-globulins
 Y-globulins


α and β globulins are synthesized in the
liver.

Y globulins are synthesized in plasma cells
and B-cells of lymphoid tissues (Reticulo-
endothelial system)

Synthesis of Y globulins is increased in
chronic infections, chronic liver diseases,
auto immune diseases, leukemias,
lymphomas and various other malignancies.


 They are glycoproteins
Based on electrophoretic mobility , they are
sub classified in to α1 and α2 globulins
α1 globulins
Examples-
α1antitrypsin
Orosomucoid (α1 acid glycoprotein)
α1-fetoprotein (AFP)


α1-antitrypsin
Also called α1-antiprotease
It is a single-chain protein of 394 amino acids,
contains three oligosaccharide chains
 It is the major component (> 90%) of the α 1
fraction of human plasma.
 It is synthesized by hepatocytes and
macrophages and is the principal serine protease
inhibitor of human plasma.
 It inhibits trypsin, elastase, and certain other
proteases by forming complexes with them.


At least 75 polymorphic forms occur, many
of which can be separated by electrophoresis
The major genotype is MM, and its
phenotypic product is PiM
A deficiency of this protein has a role in
certain cases (approximately 5%) of
emphysema.
This occurs mainly in subjects with the ZZ
genotype, who synthesize PiZ, and also in
PiSZ heterozygotes, both of whom secrete
considerably less protein than PiMM
individuals.


Emphysema-
Normally antitrypsin
protects the lung
tissue from
proteases(active
elastase) released from
macrophages
Forms a complex
with protease and
inactivates it.
In its deficiency, the
active elastase
destroys the lung
tissue by proteolysis.


Smoking and Emphysema-A methionine
(residue 358) of α1-antitrypsin is involved in its
binding to proteases.
Smoking oxidizes this methionine to
methionine sulfoxide and thus inactivates it.
Affected molecules of α1-antitrypsin no longer
neutralize proteases.
This is particularly devastating in patients (eg,
PiZZ phenotype) who already have low levels of
α1-antitrypsin.
The further diminution in α 1-antitrypsin
brought about by smoking results in increased
proteolytic destruction of lung tissue,
accelerating the development of emphysema.


Cirrhosis of Liver- In this condition, molecules
of the ZZ phenotype accumulate and aggregate
in the cisternae of the endoplasmic reticulum of
hepatocytes.
Aggregation is due to formation of polymers of
mutant α 1-antitrypsin, the polymers forming via
a strong interaction between a specific loop in
one molecule and a prominent -pleated sheet in
another (loop-sheet polymerization).
 By mechanisms that are not understood,
hepatitis results with consequent cirrhosis
(accumulation of massive amounts of collagen,
resulting in fibrosis).


 Concentration in plasma- 0.6 to 1.4 G/dl
Carbohydrate content 41%
Marker of acute inflammation
Acts as a transporter of progesterone
Transports carbohydrates to the site of
tissue injury
 Concentration increases in inflammatory
diseases, cirrhosis of liver and in malignant
conditions
Concentration decreases in liver diseases,
malnutrition and in nephrotic syndrome


Present in high concentration in fetal blood
during mid pregnancy
Normal concentration in healthy adult-
< 1µg/100ml
Level increases during pregnancy
Clinically considered a tumor marker for the
diagnosis of hepatocellular carcinoma or
teratoblastomas.


important α2-globulins are-
 Clinically

 Haptoglobin
 Ceruloplasmin
 α2- macroglobulins


Itis a plasma glycoprotein that binds
extracorpuscular hemoglobin (Hb) in a tight
noncovalent complex (Hb-Hp).
The amount of Haptoglobin in human
plasma ranges from 40 mg to 180 mg of
hemoglobin-binding capacity per deciliter.
The function of Hp is to prevent loss of free
hemoglobin into the kidney. This conserves
the valuable iron present in hemoglobin,
which would otherwise be lost to the body.


The molecular mass of hemoglobin is
approximately 65 kDa
Hb-Hp complex has a molecular mass of
approximately 155 kDa.
 Free hemoglobin passes through the
glomerulus of the kidney, enters the tubules,
and tends to precipitate therein (as can happen
after a massive incompatible blood transfusion,
when the capacity of haptoglobin to bind
hemoglobin is grossly exceeded).
However, the Hb-Hp complex is too large to
pass through the glomerulus.
Thus Hp helps to conserve iron.


Concentration rises in inflammatory conditions
Concentration decreases hemolytic anemias
Half-life of haptoglobin is approximately 5
days, the half-life of the Hb-Hp complex is
about 90 minutes, the complex being rapidly
removed from plasma by hepatocytes.
Thus, when haptoglobin is bound to
hemoglobin, it is cleared from the plasma about
80 times faster than normally.
The level of haptoglobin falls rapidly in
hemolytic anemias.
Free Hp level or Hp binding capacity depicts
the degree of intravascular hemolysis.

 Copper containing α2-globulin
 Glycoprotein with enzyme activities
It has a blue color because of its high
copper content
Carries 90% of the copper present in
plasma.
Each molecule of ceruloplasmin binds six
atoms of copper very tightly, so that the
copper is not readily exchangeable.


Normal plasma concentration approximately
30mg/dL
 Enzyme activities are Ferroxidase, copper
oxidase and Histaminase.
Synthesized in liver in the form of apo
ceruloplasmin, when copper atoms get attached it
becomes Ceruloplasmin.
 Although carries 90% of the copper present in
plasma. but it binds copper very tightly, so that
the copper is not readily exchangeable.
Albumin carries the other 10% of the plasma
copper but binds the metal less tightly than does
ceruloplasmin.
Albumin thus donates its copper to tissues more
readily than ceruloplasmin and appears to be more
important than ceruloplasmin in copper transport
in the human body.


Normal level- 25-50 mg/dl
Low levels of ceruloplasmin are found in
Wilson disease (hepatolenticular
degeneration), a disease due to abnormal
metabolism of copper.
The amount of ceruloplasmin in plasma is
also decreased in liver diseases, mal nutrition
and nephrotic syndrome.


Major component of α2 proteins
Comprises 8–10% of the total plasma protein in
humans.
Tetrameric protein with molecular weight of
725,000.
Synthesized by hepatocytes and macrophages
Inactivates all the proteases and thus is an
important in vivo anticoagulant.
Carrier of many growth factors
Normal serum level-130-300 mg/dl
Concentration is markedly increased in nephrotic
syndrome, since other proteins are lost through
urine in this condition.


β Globulins of clinical importance are –
 Transferrin
 C-reactive protein
Haemopexin
Complement C1q
β Lipoprotein(LDL)


Transferrin (Tf) is a β 1-globulin with a molecular
mass of approximately 76 kDa.
 It is a glycoprotein and is synthesized in the
liver.
About 20 polymorphic forms of transferrin have
been found.
It plays a central role in the body's metabolism of
iron because it transports iron (2 mol of Fe3+ per
mole of Tf) in the circulation to sites where iron is
required, eg, from the gut to the bone marrow and
other organs.
Approximately 200 billion red blood cells (about
20 mL) are catabolized per day, releasing about 25
mg of iron into the body—most of which is
transported by transferrin.


There are receptors (TfR1 and TfR2) on the surfaces
of many cells for transferrin.
It binds to these receptors and is internalized by
receptor-mediated endocytosis.
The acid pH inside the lysosome causes the iron to
dissociate from the protein.
The dissociated iron leaves the endosome via DMT1
to enter the cytoplasm.
ApoTf is not degraded within the lysosome.
Instead, it remains associated with its
receptor, returns to the plasma
membrane, dissociates from its receptor, reenters
the plasma, picks up more iron, and again delivers
the iron to needy cells.
Normally, the iron bound to Tf turns over 10–20
times a day.


The concentration of transferrin in plasma is
approximately 300 mg/dL.
This amount of transferrin can bind 300 g of
iron per deciliter, so that this represents the
total iron-binding capacity of plasma.
However, the protein is normally only one-third
saturated with iron.
In iron deficiency anemia, the protein is even
less saturated with iron, whereas in conditions of
storage of excess iron in the body
(eg, hemochromatosis) the saturation with iron is
much greater than one-third.


Increased levels are seen in iron deficiency
anemia and in last months of pregnancy
 Decreased levels are seen in-
Protein energy malnutrition
Cirrhosis of liver
 Trauma
Acute myocardial infarction
Malignancies
Wasting diseases


So named because it reacts with C-
polysaccharide of capsule of pneumococci
Molecular weight of 115-140 kD
Synthesized in liver
Can stimulate complement activity and
macrophages
Acute phase protein- Concentration rises in
inflammatory conditions
Clinically important marker to predict the
risk of coronary heart disease


 Molecular weight 57,000-80,000
Normal level in adults-0.5 to 1.0 gm/L
Low level at birth, reaches adult value within
first year of life
Function is to bind haem formed from
breakdown of Hb and other haemoproteins
Low level- found in hemolytic disorders, at
birth and drug induced
High level- pregnancy, diabetes mellitus,
malignancies and Duchenne muscular dystrophy


First complement factor to bind antibody
Binding takes place at the Fc region of IgG or Ig
M
Binding triggers the classical complement
pathway
Thermo labile, destroyed by heating
Normal level – 0.15 gm/L
Molecular weight-400,000
Can bind heparin and bivalent ions
Decreased level is used as an indicator of
circulating Ag –Ab complex.
 High levels are found in chronic infections


 They are immunoglobulins with antibody
activity
They occupy the gamma region on
electrophoresis
Immunoglobulins play a key role in the
defense mechanisms of the body
There are five types of immunoglobulins
IgG, IgA, IgM, IgD, and IgE.


Immunoglobulin Major Functions

IgG Main antibody in the secondary
response. Opsonizes bacteria, Fixes
complement, neutralizes bacterial
toxins and viruses and crosses the
placenta.

Secretory IgA prevents attachment of
IgA bacteria and viruses to mucous
membranes. Does not fix complement.

Produced in the primary response to
an antigen. Fixes complement. Does
IgM
not cross the placenta. Antigen
receptor on the surface of B cells.
IgD Uncertain. Found on the surface of
many B cells as well as in serum.
IgE Mediates immediate hypersensitivity
Defends against worm infections. Does

Also called clotting factor1
Constitutes 4-6% of total protein
Precipitated with 1/5 th saturation with ammonium
sulphate
Large asymmetric molecule
Highly elongated with axial ratio of 20:1
Imparts maximum viscosity to blood
Made up of 6 polypeptide chains
Chains are linked together by S-S linkages
Amino terminal end is highly negative due to the
presence of glutamic acid
Negative charge contributes to its solubility in
plasma and prevents aggregation due to electrostatic
repulsions between the fibrinogen molecules.

Name Compounds transported
Albumin Fatty acids, bilirubin, hormones,
calcium, heavy metals, drugs etc.
Prealbumin-(Transthyretin) Steroid hormones thyroxin, Retinol
Retinol binding protein Retinol (Vitamin A)
Thyroxin binding protein(TBG) Thyroxin
Transcortin(Cortisol binding protein) Cortisol and corticosteroids
Haptoglobin Hemoglobin
Hemopexin Free haem
Transferrin Iron
HDL(High density lipoprotein) Cholesterol (Tissues to liver)
LDL(Low density lipoprotein) Cholesterol(Liver to tissues)


The levels of certain proteins may increase in
blood in response inflammatory and
neoplastic conditions, these are called Acute
phase proteins.
Examples-
C- reactive proteins
Ceruloplasmin
Alpha -1 antitrypsin
Alpha 2 macroglobulins
Alpha-1 acid glycoprotein


The levels of certain proteins are decreased
in blood in response to certain inflammatory
processes.
Examples-
Albumin
Transthyretin
Retinol binding protein
Transferrin


1) Bence – Jone’s proteins
Abnormal proteins- monoclonal light chains
Present in the urine of a patient suffering from multiple
myeloma (50% of patients)
Molecular weight 45,000
Identified by heat coagulation test
Best detected by zone electrophoresis and
immunoelectrophoresis
2)Cryoglobulins
These proteins coagulate when serum is cooled to very
low temperature
Commonly monoclonal IgG or IgM or both
Increased in rheumatoid arthritis, multiple myeloma,
lymphocytic leukemia, lymphosarcoma and systemic lupus
erythematosus


Nutritive
Fluidexchange
Buffering
Binding and transport
Enzymes
Hormones
Blood coagulation
Viscosity
Defense
Reserve proteins
Tumor markers
Antiproteases


Hyperproteinemia- Levels higher than 8.0gm/dl
Causes-
 Hemoconcentration- due to dehydration,
albumin and globulin both are increased
Albumin to Globulin ratio remains same.
Causes- Excessive vomiting

Diarrhea
Diabetes Insipidus
Pyloric stenosis or obstruction

Diuresis
Intestinal obstruction


1)Polyclonal-
 Chronic infections
 Chronic liver diseases
 Sarcoidosis
 Auto immune diseases
2) Monoclonal
 Multiple myeloma
 Macroglobulinaemia
 Lymphosarcoma
 Leukemia
 Hodgkin’s disease


Decease in total protein concentration
Hemodilution- Both Albumin and globulins are
decreased, A:G ratio remains same, as in water
intoxication
 Hypoalbuminemia- low level of Albumin in
plasma
Causes-
Protein losing enteropathy
Severe liver diseases
Mal nutrition or malabsorption
Extensive skin burns
Pregnancy
 Malignancy


Losses from body- same as albumin- through
urine, GIT or skin
Decreased synthesis
Transient neonatal
 Primary genetic deficiency
Secondary – drug induced (Corticosteroid
therapy), uremia, hematological disorders
AIDS(Acquired Immuno deficiency syndrome)


Plasma proteins

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Plasma proteins