Download Special aspects of renal metabolism

Special aspects of
renal metabolism
Mahmoud A. Alfaqih BDS PhD
Jordan University of Science and Technology
Outline
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Transport of amino acids into cells
Metabolism of urea
Metabolism of creatinine
Clinical significance of urea and creatinine
measurements in the plasma
Overview
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Unlike fats and carbohydrates, amino acids are not stored by the body
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Amino acids must be obtained from the diet, synthesized de novo, or
produced from normal protein degradation
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Any amino acids in excess of the biosynthetic needs are rapidly degraded
 Catabolism of amino acids involves two phases:
1. The removal of the α-amino groups (by transamination and subsequent
oxidative deamination) forming ammonia and the corresponding α-keto acid
2. The carbon skeletons of the α-ketoacids are converted to intermediates of
energy producing pathways
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A portion of ammonia is excreted unchanged in urine, the remaining is
converted into urea and excreted in urine
Special aspects of renal metabolism
TRANSPORT OF AMINO ACIDS INTO
CELLS
Transport of amino acids into cells
 The extracellular concentration of free amino is significantly lower
than inside the cells
 The concentration gradient is maintained through active transport
(requires ATP) that moves amino acids into cells
 Seven different transport systems are known that have overlapping
specificities for different amino acids
 The small intestine and the proximal tubule of the kidney share the
same transport systems for amino acid uptake
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A defect in any of the systems results in an inability to absorb amino
acids into the gut and into the kidney tubules
Clinical correlation:
Cystinuria
 An inherited disorder caused by a defect in the uptake system of
dibasic amino acids (Cystine, Ornithine, Arginine, Lysine)
 All four amino acids appear in the urine.
 Cystinuria occurs at a frequency of 1 in 7,000 individuals.
 The most common genetic error of amino acid transport.
 The disease is characterized by the precipitation of cystine to form
kidney stones which can block the urinary tract.
 Hydration is an important part of treatment.
Special aspect of renal metabolism
METABOLISM OF UREA
General structure of amino acids
Removal of nitrogen from amino acids:
Overview
 The presence of the α-amino group keeps amino acids safely locked away
from oxidative breakdown
 Removing α-amino group is obligatory in the catabolism of all amino acids
 Once removed, nitrogen can be incorporated into other compounds or
excreted, with the carbon skeletons metabolized
 Transamination and oxidative deamination will provide ammonia and
aspartate (sources of urea nitrogen)
Transamination: the funneling of amino groups
into Glutemate
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The first step in the catabolism of most amino acids is the transfer of their αamino group to α-ketoglutarate
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The products are an α-keto acid (derived from the original amino acid) and
glutamate
 Glutamate produced by transamination can be:
1. Oxidatively deaminated (Glutemate dehydrogenase)
2. Used as an amino group donor in the synthesis of amino acids
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Transamination is catalyzed by a group of enzymes known as
aminotransferases
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Aminotransferases are found in the cytosol and mitochondria of cells
throughout the body
Substrate specificity of aminotransferases
 Each aminotransferase is specific for one or a few amino
group donors
 Aminotransferases are named after the specific amino
group donor
 Acceptor is always α-ketoglutarate
 Two clinically important aminotransferase reactions are
catalyzed by alanine aminotransferase (ALT) and
aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
 Formerly called glutamate-pyruvate transaminase (GPT)
 The enzyme catalyzes the transfer of the amino group of
alanine to α-ketoglutarate, resulting in the formation of
pyruvate and glutamate
 Bi-directional reaction
 During amino acid catabolism, functions in the direction
of glutemate synthesis
 Glutemate is a collector of amino groups from alanine
Alanine aminotransferase
Aspartate aminotransferase (AST)
 Formerly called glutamate-oxaloacetate transaminase
(GOT)
 AST is an exception to the rule that aminotransferases
funnel amino groups to form glutamate
 AST transfers amino groups from glutamate to
oxaloacetate, forming aspartate (during catabolism)
 Aspartate is used as a source of nitrogen in the urea
cycle
Aspartate aminotransferase
Diagnostic value of ALT and AST
 Aminotransferases are intracellular enzymes, with the low levels
found in the plasma
 Elevated plasma levels of aminotransferases indicate damage to
cells rich in these enzymes
 Physical trauma or a disease process cause cell lysis, causing
release of intracellular enzymes into the plasma
 AST and ALT are of particular diagnostic value when found in the
plasma
Liver disease
 Plasma AST and ALT are elevated in nearly all liver
diseases
 ALT and AST are particularly high in severe viral
hepatitis, toxic injury, and prolonged circulatory collapse
 ALT is more specific than AST for liver disease
 AST is more sensitive because the liver contains larger
amounts of AST
Non-hepatic disease
 ALT and AST may also be elevated in non-hepatic disease, such as
myocardial infarction and muscle disorders
Glutamate dehydrogenase: the oxidative
deamination of amino acids
 Oxidative deamination by glutamate dehydrogenase
results in the release of ammonia
 This reaction occurs in the liver and kidney
 The reaction produces α-ketoglutarate and ammonia
(source of nitrogen in urea synthesis)
Glutamate dehydrogenase
Direction of reaction
 It depends on the relative
concentrations of glutamate,
α-ketoglutarate, and ammonia,
and the ratio of oxidized to
reduced coenzymes
 The reaction can also be used
to synthesize glutemate from
α-ketoglutarate
Allosteric regulators
 ATP and GTP are allosteric
inhibitors
 ADP and GDP are allosteric
activators
Transport of ammonia to the liver
 Two mechanisms of transport of ammonia from the peripheral
tissues to the liver
1.
In the form of glutamine
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Used by most tissues.
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Uses glutamine synthetase to combine ammonia with
glutemate to form glutamine
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Glutamine transported to the liver
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Glutamine is cleaved in the liver into glutemate and
ammonia by glutaminase
Transport of ammonia to the liver
2. In the form of alanine
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Used primarily by the muscle.
Transamination of pyruvate into alanine.
Alanine is transported to the liver by the blood.
In the liver, alanine is converted back into pyruvate
releasing free ammonia (transamination)
 Pyruvate can be used by the liver to make glucose
 The above pathway is called glucose-alanine cycle
Urea cycle
 Urea is the major disposal form of amino groups derived
from amino acids.
 Urea accounts for 90% of the nitrogen-containing
components of urine.
 One nitrogen of the urea molecule is supplied by free
NH3, and the other nitrogen by aspartate
 Glutamate is the immediate precursor of both ammonia
and aspartate
Urea Cycle
Fate of urea
 Urea diffuses from the liver, and is transported in the blood to the
kidneys, where it is filtered and excreted in the urine.
 A portion of the urea diffuses from the blood into the intestine, and is
cleaved to CO2 and NH3 by bacterial urease
 This ammonia is partly lost in the feces, and is partly reabsorbed
into the blood.
Overall stoichiometry of the urea cycle
 The synthesis of urea is irreversible, with a large,
negative ΔG.
 One nitrogen of the urea molecule is supplied by free
NH3, and the other nitrogen by aspartate.
 Glutamate is the immediate precursor of both nitrogens:
 Through oxidative deamination of glutemate
dehydrogenase (releases free ammonia)
 Transamination reaction with oxaloacetate which
produces Aspartate
Regulation of urea cycle
 Formation of carbamoyl phosphate is the rate limiting
step in urea cycle, catalyzed by carbamoyl phosphate
synthetase I
 N-Acetylglutamate is an essential activator for carbamoyl
phosphate synthetase I
 N-Acetylglutamate is synthesized from acetyl coenzyme
A and glutamate by N-acetylglutamate synthase
 Arginine is an activator of N-acetylglutamate synthase
Hyperammonemia
 Levels of serum ammonia are normally low (5–50
µmol/L)
 The capacity of the hepatic urea cycle exceeds the
normal rates of ammonia generation
 Genetic defects of the urea cycle, or liver disease will
cause blood levels of ammonia to rise
 Hyperammonemia is a medical emergency, because
ammonia has a direct neurotoxic effect on the CNS
Acquired hyperammonemia
 Liver disease is a common cause of hyperammonemia in
adults
 Common causes include: viral hepatitis, ischemia,
hepatotoxins, cirrhosis, biliary obstruction leading to
collateral circulation around the liver
Hereditary hyperammonemia
 Genetic deficiencies of each of the five enzymes of the urea cycle
have been described
 Ornithine transcarbamoylase deficiency is the most common (Xlinked)
 Failure to synthesize urea leads to hyperammonemia during the first
weeks following birth
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Treatment includes limiting protein and administering compounds
that bind covalently to amino acids and cause their excretion
Special aspect of renal metabolism
CREATININE METABOLISM
Creatine: Overview
 Creatine phosphate (phosphocreatine) is found in muscle.
 Creatine Phosphate is a high-energy compound that can
donate a phosphate group to ADP to form ATP.
 Creatine phosphate provides a small, rapidly mobilized
reserve of high-energy phosphates .
 Creatine phosphate is used to maintain the levels of ATP
during the first few minutes of intense contraction.
 The amount of creatine phosphate is proportional to the
muscle mass
Synthesis of Creatine
 Creatine is synthesized from glycine and the guanidino group of
arginine, plus a methyl group from SAM
 Creatine is reversibly phosphorylated to creatine phosphate by
creatine kinase, using ATP
 N.B: The presence of creatine kinase in the plasma is used in the
diagnosis of myocardial infarction
Degradation of Creatine
 Creatine and creatine phosphate spontaneously cyclize to form
creatinine (Excreted in urine)
• The amount of creatinine excreted can be used to estimate muscle
mass
• When muscle mass decreases (paralysis, muscular dystrophy), the
creatinine content of the urine falls.
• Any rise in blood creatinine is an indicator of kidney malfunction,
because creatinine is rapidly removed from the blood and excreted.