Tissue-specific metabolism

Liver
Main site of AA degradation
(deamination) & urea synthesis for
nitrogen excretion
During fasting, = main site of
gluconeogenesis, using carbon skeletons from
AAs
Major role in synthesis of
tripeptide glutathione
lntestine
Enterocytes take up glutamine &
metabolise it to alanine to produce
energy
Enterocytes = only cells to contain
glutamate reductase, the synthetic enzyme
for citrulline
Citrulline from gut metabolised to arginine in
liver, then to ornithine to increase capacity of
urea cycle during periods of increased protein
uptake
Skeletal muscle
Broken down during starvation
for gluconeogenesis in liver
Main AAs released = alanine &
glutamine
Alanine transported by blood to
liver for deamination &
gluconeogenesis
Glutamine taken up by
enterocytes for energy, & released
as alanine
Renal Cortex
Only tissue other than liver to perform
gluconeogenesis: capacity of up to 10& of total
glucose generation
Converts citrulline via arginine to creatine, used
by skM to store high-energy phosphate bonds
as creatine phosphate
Creatine phosphate
spontaneously forms creatine
Creatine excreted by kindeys;
blood level used to assess renal
function
Major site of carnitine
synthesis (with liver to lesser
extent) Carnitine used in FA B-oxidation
Urea Cycle
Under all conditions, body needs
to excrete amino groups (ie.
ammonia)
On Western diet, protein intake
generally >> need
Cannot store excess AAs
Use/store carbon skeletons as energy
source; excrete unwanted amino
groups
lf protein intake << need
Protein catabolism occurs to
free carbon skeletons for
energy
Excess amino groups need to
be excreted
Free ammonia toxic: blood levels
need to be kept low
(25-40microM)
lf ammonium levels rise, NH4+ reacts
with alpha-ketoglutarate to form
glutamate
At high levels in brain, this reduces
rate of ATP formation, starving cells of
energy
Healthy adults in 'nitrogen balance'
~80% of excess nitrogen excreted as
urea; remainder as free NH4+ &
creatine
Most urea synthesised by liver; rate
strictly controlled to prevent ammonia
build-up
Urea used in kidney as part of
urinary concentrating
mechanism
Urea cycle describes formation of urea from one
free ammonium ion & one donated from
aspartate
Occurs partly in mitochondrial
matrix, partly in cytoplasm
lnvolves 2 AAs not found in
proteins: ornithine & citrulline
Control
Acute Via Carbamoyl-phosphate synthetase
Regulated by [N-acetyl glutamate], formed by
N-acetyl glutamate synthase, stimulated by urea
cycle intermediate arginine
Chronic
Enzymes induced over 24-36hrs in
response to increased ammonia levels in
liver cells
Ammonia levels can vary 10-20-fold with diet &
under starvation conditions when muscle broken
down
Under prolonged starvation conditions, ability
for enzyme (protein) synthesis may be
compromised
Protein from diet (~70g/day)
broken down by sequential protein
digestion
Enzymes of protein degradation
= peptidases
From Stomach Pepsin
Secreted by chief cells of stomach as
pepsinogen, activated by pH<5 or by active
pepsin
Cleave internal peptide
bonds to release large
peptide fragments
Peptide fragments in duodenum stimulate
CCK production, stimulating pancreatic
secretion
Stomach acidity denatures proteins,
makes more susceptible to
hydrolysis
From Pancreas
Pancreatic secretion contains various
proteolytic enzymes active at neutral
pH:
Endopeptidases (serine proteases)
Trypsin
Chymotrypsin
Elastase
Exopeptidases
Carboxypeptidases A & B Remove last AA from peptide chain
Aminopeptidases Remove first AA from peptide chain
Produce mixture of AAs & small
peptides up to 6AAs long
(oligopeptides)
Neutral intestinal lumen achieved by secretion
of bicarbonate-rich pancreatic juice to
neutralise gastric acid
All proteases secreted as inactive precursors,
'zymogens': trypsinogen, chymotrypsinogen,
proelastase & procarboxypeptidase A & B
Trypsin activated by enteropeptidase from
enterocytes of small intestine, & by active
trypsin
Trypsin activates all other
proteolytic enzymes
Diseases eg. pancreatitis, Cystic Fibrosis, which
interfere with pancreatic secretions, prevent full
protein digestion --> malabsorption &
malnutrition
Overcome by supplying preparations of
exogenous pancreatic enzymes, or dietary
supplements of easily-digested proteins
Lumenal (Brush-border) membrane of
enterocytes contain enzymes that continue
digestion
Endopeptidases, aminopeptidases &
dipeptidases continue digestion to dipeptides,
tripeptides & free AAs
Mixture of di- & tri-peptides &
AAs taken up by enterocytes
Proton-couple transporter for peptides
Na-coupled transporter for AAs
lntracellularly, any
peptides broken down to
free AAs
AAs leave enterocytes via
basolateral membrane & enter
circulation
Some hydrolysis-resistant
peptides (& antibiotics) may
leave cell intact
Amino Acids
Essential AAs: Those the body
cannot make
Arginine, Histidine, lsoleucine, Leucine, Lysine,
Methionine, Phenylalanine, Threonine,
Tryptophan, Valine
'Private Tim Hill,' PVT TlM HLL'
Are His lsolated Looks Lies?
Merely Philosophies, Trying
Valiantly.
Arginine can be synthesised in
body, but not in large enough
quantities
Dietary lack of an essential AA -->
inability to synthesise proteins
containing
Non-essential: can be made by body
Alanine, aspartate, asparagine, cysteine,
glutamate, glutamine, glycine, proline, serine,
tyrosine
Variety of uses/fates:
Protein synthesis
Hormones, eg. adrenaline
Neurotransmitters, eg. 5-HT
Deaminated
Carbon skeleton oxidised in TCA cycle
Carbon skeleton converted to
glucose via gluconeogenesis Possible for 'glucogenic' AAs
Via pyruvate
Alanine, Glycine, Cysteine,
Serine, Threonine
Via TCA intermediates oxaloacetate,
fumarate, succinate & alpha-ketoglutarate
Asparagine & Aspartate -->
oxaloacetate
Carbon skeleton converted to
acetyl CoA or acetoacetyl CoA
for FA synthesis Possible for 'ketogenic' AAs Only leucine & lysine solely ketogenic
Breakdown Breakdown Breakdown Breakdown Oxidation
Excess AAs cannot be stored:
carbon skeletons used as energy
source
Transamination
Aminotransferases (transaminases) catalyse
transfer of NH3+ from AA to an alpha-ketoacid:
pyruvate, oxaloacetate, or - usually - alpha-ketoglutarate
New amino acid & new ketoacid formed
lf acceptor = a-ketoacetate, forms glutamate:
provides pool of amino groups for making other
non-essential AAs, or for deamination
lf original amino acid = alanine,
glycine etc, ketoacid produced =
pyruvate
Each AA has own specific
aminotransferase
Reactions easily reversible,
require to energy input
Deamination
Glutamate deaminated by
glutamate dehydrogenase
Pooling of excess amino groups in
glutamate means only 1 deamination
pathway required
Deamination pathway regenerates alpha-ketoglutarate
& free ammonium (NH4), & an
NADH
Allosterically stimulated by increased ADP &
GDP: these signal that AAs required as energy
source. lnhibited by ATP/GTP
Occurs in mitochondria of liver cells
Major fate of NH4+ =
incorporation into urea by
liver as soluble, non-toxic
way of eliminating excess
ammonium
Renal cortex can also deaminate
glutamate
Ammonium used to assist with
acidifying urine
Mechanism conserves bicarbonate, which
would otherwise need to be used in urea
synthesis
Other sites of ammonium
production include:
Brain
Breakdown of GABA to succinate
& NH4+
Ammonium ion combined with alpha-ketoglutarate
to produce glutamate, which is
transported to liver for deamination & urea
production
Muscle
Natural protein turnover, muscle catabolism in
starvation & breakdown of excess ADP during
severe exercise
Ammonium ion + alpha-ketoglutarate
--> glutamate
Glutamate used to transaminate pyruvate,
forming alanine & regenerating alpha-ketoglutarate
Alanine released into
bloodstream & taken up by liver
Deamination of alanine releases pyruvate
for oxidation in TCA cycle or
gluconeogenesis
lntestinal Cells Glutamine used as energy source
Amino Acid Metabolism Amino Acid Metabolism Amino Acid Metabolism Amino Acid Metabolism