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Biochemistry of Albumin Metabolism, SERUM ALBUMIN CONCENTRATION, A…
Biochemistry of Albumin
Metabolism
ALBUMIN GENE
Member of the albuminoid gene superfamily along
with
a-fetoprotein
All these genes are located on chromosome 4 in
humans
most abundant plasma protein
in fetal life
vitamin D-binding protein
afamin (vitamin E-binding glycoprotein)
Albumin is the most abundant plasma protein
(50% of total protein content) in postnatal life
Analbuminemia
Very rare autosomal recessive disorder
caused by
mutations in
albumin gene
Characterized by
absence
or
very low levels of albumin
Diagnosed in
adulthood
Mild edema, hypotension,
fatigue, hyperlipidemia and
occasionally a peculiar lower
body lipodystrophy
More severe in the fetus or during early infancy where it can lead to fetal or neonatal death
Bisalbuminemia
(or Alloalbuminemia)
Relatively rare hereditary
(permanent) condition
caused by
mutations in albumin gene
or
acquired (transient) condition
induced by
prolonged use of
antibiotics
or
acute pancreatitis
Characterized by
the presence
of two distinct albumin bands on
serum protein electrophoresis
Some albumin variants have altered affinity for steroid hormones, thyroxine or drugs
Familial Dysalbuminemic Hyperthyroxinemia (FDH)
Rare autosomal dominant condition
caused by
mutations in
albumin gene
Characterized by
up to 60-fold increase in the affinity of
albumin for thyroxine (T4)
Consistently
elevated total T4
normal free T4 values
normal thyroid stimulating hormone TSH levels
Clinically euthyroid and asymptomatic individuals
Individuals do not require treatment, but may be at risk for unnecessary laboratory testing and possibly even unnecessary medication
ALBUMIN SYNTHESIS
synthesized by the liver
Under physiological conditions
only ~20% of hepatocytes are committed to the production of 10-15 g of albumin per day
Therefore
the liver has a large functional reserve,
so that it can increase the synthesis of this protein by 3-4 times, if necessary
initially synthesized at ribosomes on the rough
endoplasmic reticulum of the hepatocytes
as
preproalbumin
leading to
formation of proalbumin (inactive form)
released from
the rough
endoplasmic reticulum
Furin cleaves 6 additional amino acids from the C-terminus of
in the Golgi-derived vesicles
leading to
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signal peptidase cleaves 18 amino acids (signal peptide) from the N-terminus of --->
Plasma half-life ~20 days
REGULATION OF
ALBUMIN SYNTHESIS
Down-regulation of albumin synthesis
Nutrition
A diet poor in proteins reduces albumin synthesis
Kwashiorkor
(the sickness the baby gets
when the new baby comes)
hypoalbuminemia
Nutritional disorder most often seen in
developing countries
It is a form of malnutrition caused by a
lack of protein in the diet
Major biochemical feature is
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Inflammation
Cytokines such as
tumor necrosis factor (TNFa)
inhibit the synthesis of albumin
interleukin-1 (IL-1)
Up-regulation of albumin synthesis
Hormones
Insulin, cortisol, thyroid hormones, growth hormone, sex hormones
induce the albumin synthesis
ALBUMIN STRUCTURE
It is comprised of 585 amino acids (~66 kDa)
It is rich in charged amino acids
histidine, arginine, glutamine, aspartic acid
It has a heart shape in x-ray
crystallography
(an ellipsoid shape in plasma in order not to increase its viscosity
The mature, circulating molecule is
arranged in a series of α-helices
stabilized by 17 disulfide bonds
comprises three homologous domains (I–III)
Each of these domains
has two subdomains (A and B) composed of 4 and 6 α-helices
These domains contain
2 sites that play a significant role in transporting
hydrophobic molecules (Sudlow sites 1 and 2)
7 fatty acid-binding sites (FA1-7)
1 heme-binding site
4 metal-binding sites, including sites A and B, N-terminal site (NTS) and Cys34
Numerous small ligand-binding sites
ALBUMIN DISTRIBUTION
ALBUMIN DEGRADATION
degraded in most organs of the body
Muscle and skin are the primary sites of degradation,
accounting for 40% to 60% of all albumin degradation
The liver, despite its high rate of protein metabolism,
degrades 15% or less of the total
The kidneys are responsible for about 10%
another 10% leaks through the stomach wall into the gastrointestinal tract
Specialized epithelial cells endocytose albumin
Albumin enters early endosomes
From there it is transferred to late endosomes having endosomal neonatal Fc receptor (FcRn) in the membrane
At pH of 5-6, the protein binds strongly to the
receptor at a 1:1 stoichiometry
Albumin bound to FcRn in the endosomes could leave the cell by:
Recycling (Albumin is captured on one side of the cell, travels across the cell and ejected on the same side of the cell)
Transcytosis (Albumin is captured on one side of the cell, drawn across the cell, and ejected on the other side of the cell)
Albumin which does not bind to FcRn
goes to degradation in the lysosome
FUNCTIONS OF ALBUMIN
Maintenance of oncotic or colloid osmotic pressure (COP) within the vascular compartments (80% of COP)
COP is the osmotic pressure exerted by large molecules that do not diffuse readily across the capillary membrane preventing leaking of fluids into the extravascular spaces
Each gram of albumin is capable of holding
18 ml of water within the intravascular space
Binding, transportation and distribution of
endogenous and exogenous ligands
e.g.
ions, metals, hormones, long chain fatty
acids, therapeutic drugs and metabolites
Antioxidant activity (free radical trapping
capacity)
Maintenance of acid-base balance
high histidine content contributes to albumin’s buffering capacity
POST-TRANSLATIONAL MODIFICATIONS OF ALBUMIN
due to
Metabolic changes associated with various diseases
These include
oxidation, glycation, nitrosylation,
guanylation, dimerization, and truncation
This leads to
formation of numerous albumin
variants that become more abundant in the blood
ISCHEMIA – MODIFIED ALBUMIN
Under non physiological conditions
hypoxia, oxidative stress,
acidosis
there is production of
free radicals
can cause
oxidation or truncation at the NTS
(Asp1-Ala2-His3-Lys4) of albumin
leading to
reduction of the affinity of NTS to transitional metals
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release of
free fatty acids (FFA) into the plasma
High plasma FFA levels can
change the conformation of
albumin
hampering
the binding of Co2+
to its binding site
Albumin cobalt binding (ACB) test
Measurement of ischemiamodified albumi
FDA-approved biomarker for early
detection of myocardial infarction
Used as biomarker for numerous
other pathological conditions
ALBUMIN METABOLISM IN
NEPHROTIC SYNDROME
Nephrotic syndrome is characterized by
Proteinuria (mostly albuminuria)
Hypoalbuminemia (< 30 g/L)
↑ Cholesterol synthesis
(lipogenesis)
↓ Lipoprotein degradation
Inadequate colloid osmotic pressure
Vascular fluid leakage to extravascular space
Edema
Hyperlipidemia
SERUM ALBUMIN
CONCENTRATION
Serum albumin concentration is a strong prognostic indicator of morbidity and mortality in both sick and seemingly healthy individuals
is the result of
Synthesis
Degradation
Distribution
High concentrations are unusual
HYPERALBUMINEMIA
The only causes are
Water depletion
Intravenous infusion of plasma
HYPOALBUMINEMIA
due to
Decreased synthesis
Malnutrition (Protein-poor diet)
Liver disease
Redistribution
Ascites
Sepsis
Increased loss
Protein‐losing
nephropathy,
enteropathy,
dermatopathy
Loss of plasma
e.g. from burns
Dilution
Intravenous infusion of
fluid
A healthy kidney does not let albumin pass into the urine
in renal disease, there is increased permeability of
the glomerular capillaries to plasma proteins
Albumin pass into the urine
Albumin loss
