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Catabolism of Carbon
Skeletons of AAs
Prof. Dr. Arzu SEVEN
• The pathways of amino acid catabolism
normally accounts for only 10-15% of
human body's energy production.
• 20 catabolic pathways converge to form
only 6 major products, all of which enter
citric acid cycle.
• From there, C skeletons are diverted to
gluconeogenesis or ketogenesis or are
completely oxidized to CO2 and H2O .
• Amino acids may be either glucogenic or
ketogenic .
• These amino acids that feed carbons into TCA
cycle at the level of α-ketoglutarate, succinyl
coA, fumarate or oxaloacetate and those that
produce pyruvate ,can produce glucose via
gluconeogenesis and are glucogenic (alanine,
arginine, asparagine,aspartic acid, glycine,
histidine, methionine, proline, serine, valine)
• Those amino acids that feed carbons at
the level of acetyl-coA or acetoacetyl coA
are ketogenic (leucine, lysine)
• Leucine is an exclusively ketogenic AA ,its
degradation makes a substantial
contribution to ketosis under starvation
• Both glucogenic and ketogenic AAs
isoleucine, phenylalanine, threonine,
tryptophan, tyrosine
• Amino acids that we can not synthesize
are termed ESSENTİAL amino acids
• Cysteine is not generally considered as an
essential AA because it can be derived
from non-essential amino acid serine, its
sulfur must come from essential amino
acid methionine.
• Tyrosine is not required in the diet, but
must be derived from essential amino acid
phenylalanine.
Conversion of AA to Specialized
Products
• Important products derived from AA
include heme, purines, pyrimidines,
hormones, neurotransmitters and
biologically active peptides.
Glycine
• Water-soluble glycine conjugates:
glycocholic acid and hippuric acid formed
from food additive benzoate.
• Drugs or drug metabolites with carboxyl
groups are excreted in the urine as glycine
conjugates.
• Creatine and glutathione
• Nitrogen and α-C of glycine are,
incorporated into the pyrole rings and
methylene bridge carbons of heme.
• 4,5, and 7 atoms of purine glycine is
degraded via 3 pathways:
• Nonketotic hyperglycinemia:
Defect in glycine cleavage enzyme activity
• Glycine (serum)
• mental deficiency
• death in early childhood
• At high levels glycine is an inhibitory
neurotransmitter.
O
H O NH
• Glycine
Glyoxylate NAD NADHOxalate
2
2
D-Amino
Acid
oxidase
3
• Primary function of D-amino acid oxidase,
present at high levels in the kidney, is to detoxify
the ingested D-amino acids derived from
bacterial cell walls and from grilled foodstuff.
• Oxalate, from food or produced enzymatically in
kidney, has medical significance as crystals of
calcium oxalate in 75% of kidney stones.
• (urolithiasis, nephrocalcinosis, early mortality
from renal failure or hypertension)
• Several enzyme cofactors play important
roles in amino acid catabolism:
Transamination requires pyridoxal
phosphate
• One Carbon transfer requires
Biotin tetrahydrofolate and
S-adenosylmethionine
• Biotin transfers Carbon its most oxidized
state (CO2)
• Tetrahydrofolate transfers one carbon
groups in intermediate oxidation states (as
methyl groups)
• s-adenosylmethionine transfers methyl
groups (the most reduced state of carbon)
Homocystinuria
• A relatively rare autosomal recessive
condition
• Defect in methionine catabolism
• Lack of an enzyme which catalyzes the
transfer of sulfur from homocysteine to
serine though the formation of
cystathionine intermediate.
• Mental retardation , vision problems,
thrombotic strokes, coronary artery
disease at young age.
• Defective carrier-mediated transport of
cystine results in cystinosis (cystine
storage disease) with deposition of cystine
crystals in tissues and early mortality from
acute renal failure.
• In cystinuria,a defect in renal
reabsorption,cystine,lysine,arginine and
ornithine are excreted.
• The mixed disulfide of L-cysteine and Lhomocysteine,excreted by cystinuric
patients,is more soluble and reduces
formation of cystine calculi.
• β-Alanine:
• β-alanine, a metabolite of cysteine, is
present in coenzyme A and as BalanyLdipeptides (carnosine, anserine )
• Cysteine:
• A precursor of thioethanol amine portion of
coenzyme A
• A precusor of taurine that conjugates with
bile acids such as taurocholic acid
Histidine
• Histidin
Decarboxylation
(-co2)
Acid secretion
İn stomach
Histamine
Allergic
reaction
vasodilatator
• Arginine:
• Formamidine donor for creatine synthesis
• Precursor of nitric oxide, NO
(neurotransmitter, smooth muscle relaxant
and vasodilatator)
• Phosphocreatine, derived from creatine, is
an important energy buffer in skeletal
muscle.
• Creatine is synthesized from glycine,
arginine.
• Methionine, in the form of
S_adenosylmethionine, acts as a methyl
donor.
• Tryptophan, lysine, phenylalanine,
tyrosine, leucine, isoleucine and threonine
acetyl coA and/or aceto acetyl -coA
• Tryptophan:
Nicotinamide
Serotonin
indolacetate
• Principal normal urinary catabolites of
tryptophan are 5-hydroxyindolacetate and
indole-3-acetate.
• Phenylalanine
Tyrosine
Dopamine
NE
E
T3, T4
• Melanin is derived from tyrosine
• Parkinson's disease is associated with
underproduction of dopamine.It has
traditonally been treated by L-Dopa
administration.
• Over production of dopamine in the brain
may be linked to schizophrenia.
• 5 hydroxytryptamine=serotonin:
• A potent vasoconstrictor and stimulator of
smooth muscle contraction.
• Serotonin
N-acetylation
O-methylation
melatonin
5 hydroxy indolacetate
MAO
Catalyzed
oxidative
deamination
• Carcinoid(argentaffinoma)
• Tm cells that over produce serotonin.
• Glutamate decarboxylation gives rise to
GABA, an inhibitory neurotransmitter
• Its overproduction is associated with
epilectic seizures.
• GABA analogs are used in the treatment
of epilepsy and hypertension.
• γ-aminobutyrate (GABA)
• Functions in the brain as an inhibitory
neurotransmitter by altering
transmembrane potential differences.
• L-glutamate
GABA
decarboxylase
• Branched Chain AA (leucine, valine,
isoleucine) are oxidized as fuels primarily
in muscle, adipose, kidney and brain
tissue (extrahepatic tissues)
• 1-Transamınation (branced-chain amino
transferase (absent in liver)
α- AA
α- ketoacid
• 2-Oxidative
decarboxylation (by mitochondrial
branched chain α-ketoacid
dehydrogenase)
• This multimeric enzyme complex
resembles pyruvate dehydrogenase and
α-ketoglutarate dehydrogenase being
inactivated by phosphorylation and
activated by dephosphrylation.
• 5 cofactors (TPP, FAD, NAD, lipoate,
coenzyme A)
• 3-Dehydrogenation