Transcript AA Transport Associated Hereditary Disorderspww660 KB

Amino AcidTransport and
Associated Hereditary
Disorders
Prof. Dr. Arzu SEVEN
• Mechanisms of active transport of amino
acids and di-or tripeptides into intestinal
epithelial cells are similar to those
described for glucose uptake.
• At the brush border membrane Na+
dependent symporters mediating amino
acid uptake are linked to ATP-dependent
pumping out of Na+ at the contraluminal
membrane
• A similar H+-dependent symporter is present on
the brush border surface for di- and tripeptide
active transport into the cell.
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• Na-independent
transporters are present on the
contraluminal surface, allowing facilated
transport of amino acids to hepatic portal
system.
• At least 6 specific symporter systems have
been indentified for the uptake of L-amino
acids from the intestinal lumen
• These transport systems are also present
in the renal tubules and defects in their
molecular structure can lead to disease.
γ glutamyl cycle
• A metabolic cycle involving GSH as a
carrier has been implicated in the transport
of certain amino acids across the
membranes in the kidney.
• Amino acid +GSH
γ glutamyl amino
acid+cysteine + glycine
• Enzyme: γ glutamyltransferase (GGT)
located in plasma membrane
• (γ glutamyl transpeptidase)
• This reaction helps transfer certain amino
acids across the plasma membrane,
amino acid is hydrolyzed and GSH
resynthesized from cysteinylglycine.
• This cycle is present in the plasma
membrane at renal tubular cells and bile
ductule cells, and in the endoplasmic
reticulum of hepatocytes.
• γ_GT is released into the blood from
hepatic cells in various hepatobiliary
diseases.
Neutral Amino Aciduria:
Hartnup Disease
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• Hartnup disease is a genetic defect in the Nacoupled transporter that normally mediates
absorption of neutral amino acid from the lumen
of the small intestine and the proximal tubule.
• In the kidney, the inability to reabsorb
neutral amino acids from the ultrafiltrate
leads to their excretion in urine (neutral
amino aciduria).In the intestine, the defect
results in malabsorption of dietary neutral
amino acids.
• Clinical symptoms are those one would
expect for a deficiency of tryptophan with
pellagra-like features, which is an
expression of the decreased availability of
tryptophan for conversion to nicotinamide.
Cystiniuria
• Autosomal recessive disorder of intestinal
absorption and proximal tubular
reabsorption of dibasic amino acids.
• No defect in cysteine metabolism per se
• Cysteine remains in the urine
• Oxidizes to its disulfide form (cystine)
• Cystine is relatively insoluble, tends to
precipitate in the urinary tract-kidney stone
• Treatment-by restriction of dietary intake
of methionine (a biosynthetic precursor of
cysteine) + high fluid intake to keep the
urine dilute + drugs that may convert
cysteine to a more soluble compound