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Amino acid oxidation and the
production of urea
• Nitrogen excretion and the urea
cycle
• Degradation of carbon skeleton of
amino acids
Amino acids undergo degradation
under circumstances of:
• During the normal synthesis and degradation of
cellular proteins
• When dietary protein exceeds the body’s needs;
amino acids cannot be stored.
• During starvation or in diabetes mellitus, cellular
proteins are used as fuel.
Excretory forms of nitrogen
The first step in the catabolism of amino acids –
transamination by aminotransferases
(e.g. alanine
aminotransferase,
aspartate
aminotransferase)
Amino group donor for
biosynthetic pathway
(the coenzyme
form of pyridoxine
or vitamin B6)
Excretion pathway
PLP is the prothetic
group of all
aminotransferases
Alanine aminotransferase (ALT; or glutamatepyruvate transaminase, GPT)
Aspartate aminotransferase (AST; or glutamateoxaloacetate transaminase, GOT)
• After a heart attack, a variety of enzymes, including these
aminotransferases, leak from the injured heart cells into the
bloodstream. Measurements of the blood serum
concentration of the two aminotransferases by the SGPT and
SGOT test (S for serum), and of another enzyme, creatine
kinase, by the SCK test, can provide information about the
severity of the damage.
• Creatie kinases is the first heart enzyme to appear in the
blood after a heart attack; it also disappear quickly from the
blood. GOT is the next appear, and GPT follows later.
• Liver degeneration caused by carbon tetrachloride,
chloroform, or other industrial solvent is accompanied by
leakage of GOT and GPT from injured hepaocytes into blood.
Excretion pathway
Oxidative deamination
(Extrahepatic
tissues)
(Liver mitochondria)
Fix NH4+ in
extrahepatic
tissues
Release NH4+ in liver
(Blood
)
Release
NH4+ in liver
& kidney
Liver
NH4
Kidney
Biosynthesis of amino
acids (all tissues)
Urine
+
(glutamate dehydrogenase)
Carbon
skeleton
Alanine transports ammonia
from muscles to the liver via
the glucose-alanine cycle
-Low [NH4+]blood
when breakdown muscle protein for energy
(An ammonia
carrier in
blood)
Ammonia is toxic to animals
• Depletion of a-ketoglutarate to glutmate by glutamate
dehydrogenase and conversion of glutamate to glutamine
by glutamine synthetase to consume the cytosol of excess
ammonia, limiting the availability of a-ketoglutarate for the
citric acid cycle. The glutamine synthetase reaction
depletes ATP. Overall, toxic concentration of NH4+ may
interfere with the very high levels of ATP production
required to maintain brain function.
•
Depletion of glutamate in the glutamine synthetase
reaction may additional effects on the brain. Glutamate and
its derivative, -aminobutyrate (GABA), are important
neurotransmitters.
• The sensitivity of the brain to ammonia may reflect a
depletion of neurotransmitters as well as changes in
cellular ATP metabolism.
The urea cycle
liver mitochondria→.
kidney→ urine
1.Ornithine
transcarbamoylase
2. Argininosuccinate
synthetase
3. Argininosuccinate lyase
4. arginase
(Rate-limiting step)
Carbamoyl phosphate
synthetase I
HCO3
Carbamate
HCO3
HCO3
Urea
Carbamate
Ornithine
Argininosuccinate synthetase mechanism
Arginine
The overall equation of the urea cycle is
→
2 NH4+ + HCO3- + 3 ATP4- + H2O
Urea + 2 ADP3- + 4 Pi2- + AMP2- + 5 H+
- 2.5 ATP
Pathways of amino acid degradation
Several enzyme cofactors play important
roles in amino acid catabolism
Three enzyme cofactors important in one-carbon transfer reaction
Conversions of onecarbon units on
tetrahydrofolate.
Synthesis of methionine and S-adenosylmethionine
in an activated-methyl cycle
• Methionine synthase present in bacteria and
mammals uses either N5-methyl-tetrahydrofolate
or methylcobalamin derived from coenzyme B12.
• In cases of vitamin B12 deficiency, some
symptoms can be alleviated by the administration
not only of vitamin B12 but of folate.
• The methyl group of methylcobalamin is derived
from N5-methyl-tetrahydrofolate . Because the
reaction converting the N5, N10-methylene form to
the N5-methyl form of tetrahydrofolate is
irreversible, if coenzyme B12 is not available for
the synthesis of methylcobalamin, then no
acceptor is available for the methyl group of N5methyltetrahydrofolate and metabolic folates
become trapped in the N5-methyl form.
Catabolic pathways for phenylalanine and
tyrosine.
Phenylketonuria (PKU)
• A genetic defect in phenylalanine
hydroxylase, the first enzyme in the catalbolic
pathway for phenylalanine.
• The most common cause of elevated levels of
phenylalanine (hyperphenylalanine).
• Phenylalanine hydroxylase is one of a
general classes of enzymes called mixedfunction oxidases.
Role of tetrahydrobiopterin in the
phenylalanine hydroxylase reaction. Note that
NADH is required to restore the reduced form
of the coenzyme.
Branched-chain amino acids
are not degraded in the liver
• Although much of the catabolism of amino acids
takes place in the liver, the three amino acids with
branched side chains (leucine, isoleucine, and
valine) are oxidized as fuels primarily in muscle,
adipose, kidney, and brain tissue.
• These extrahepatic tissues contain an
aminotransferase, absent in liver, that acts on all
three branched-chain amino acids to produce the
corresponding a-keto acids.
• The branched-chain a-keto acid dehydrogenase
complex then catalyzes oxidative decarboxylation
of all three a-keto acids, in each case releasing
the carboxyl group as CO2 and producing the
acyl-CoA derivative.
Catabolic pathways for the three branched-chain
amino acids: valine, isoleucine, and leucine
Maple syrup urine disease
(MUSD)
• The characteristic odor imparted to the urine
by the a-keto acids, results from a defective
branched-chain a-ketoacid dehydrogenase
complex.
• Untreated, the disease results in abnormal
development of the brain, mental retardation,
and death in early infancy.
• Treatment entails rigid control of the diet,
limiting the intake of valine, isoleucine, and
leucine to the minimum required to permit
normal growth.
Summary of the glucogeneic
and ketogenic amino acids.