Documenti di Didattica
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Rod Hori
rhori@uthsc.edu
Objectives
1. Describe which molecules are important to the
assimilation and excretion of urea
A. contribute or transport nitrogen
B. steps of the urea cycle
2. Explain the cause and affects of ammonia,
Ornithine Transcarbamoylase deficiency and
Homocysteinemia
3. Recall the diseases with corresponding symptoms
and enzymes in the Tyrosine Synthesis (Phe
Degradation) pathway
4. Recall the precursors in the synthesis of the
Serine family of amino acids
5. Recall the names and describe the roles of the
Outline
I. Introduction
II. Urea Cycle
III. Synthesis
A. Arginine
B. Phenylalanine/Tyrosine
C. Alanine, Serine, Glycine, Cysteine
Amino Acid Metabolism
Absorption Transport
=
1 (Dr Albritton)
4Glycogen 3
and Fatty (3, 4, 5: AA 2 & 3-Tues and We
Acids
(Storage) 3
Figure
VII.1
Amino Acids are also used in (Energy)
Metabolism Same slide in Amino Acids -2
Glucose
Insulin
Glucagon
Cortisol
and Glutamine
Figure 38.11
Glutamine is a major carrier of nitrogen to
the liver for disposal. (Urea cycle - next class
today)
Glutamine can be deaminated and then used
Alanine can be transported from Muscle to
Liver, converted to Pyruvate and used for
Gluconeogenesis
(Glucose-Alanine Cycle)
Same slide in Amino Acids
Brain, Red Blood
Cells, Other tissues
and needs
Figure 38.9
NH3 (ammonia) or NH4+
Ammonia
(ammonium ion)
NH4+ is predominant form b/c
pKa of dissociation = 9.3
However, NH3 is important b/c
it is the form that can cross
membranes
Limit to healthy level of
ammonia in blood
Normal level of ammonia in
blood = 30-60 M
Ammonia can pass across
blood-brain barrier
-KG > Glutamic Acid >
Glutamine
Affects Citric Acid Cycle
Affects neurotransmitter levels
Key points 1
Alanine and Glutamine transported
to liver are source of nitrogen that
needs to be disposed
Glutamic Acid collects amino groups
(nitrogens) that can enter the Urea
Cycle
High levels of ammonia are toxic to
cells
Amino Acid Metabolism
(Amino Acid 1) A
Transport
1 (Dr Albritton)
3
4Fatty Acids
(Storage) (3, 4, 5: Amino Acids 2 and 3
3
Most nitrogen disposal is
performed by Urea Cycle in the
Liver
Figure 38.12
Urea Cycle
Figure 38.12
Carbamoyl phosphate synthetase I
catalyzes the formation of carbamoyl
phosphate
Figure 38.12
In the mitochondria, Citrulline is generated from
Carbamoyl phosphate and Ornithine by Ornithine
Transcarbamoylase
Mitochondria Cytosol
Figure 38.12
(enlarged)
Citrulline is transported from the
Mitochondria to the Cytoplasm
Mitochondria Cytosol
Figure 38.12
(enlarged)
In the cytoplasm, Citrulline and Aspartic
Acid react.
Figure 38.12
The Urea Cycle and Citric Acid Cycle
use common reactions
Figure 38.12
Blood Urea Nitrogen (BUN)
Blood Urea Nitrogen is a measure of blood
urea level
Patients with kidney (renal) failure have
high BUN.
Normal range = 250 700 M (8-20 mg/dl)
Disorders of the Urea Cycle
Ornithine Transcarbamoylase (OTC) deficiency
(Marks, p 718)
Most common urea cycle defect
X-linked disorder; 1 in 20,000 to 80,000
Major clinical problem increased blood
ammonia results in neuronal damage
and mental retardation
Hyperammonemia, Low to No Detectable
Citrulline and High Orotate (Orotic Acid)
Treatment: Need early intervention.
Generate low nitrogen levels by -
Low-protein diet
Drugs that conjugate (react with)
amino acids
-Benzoic acid and phenylbutyrate excretion
- Conjugated amino acids are lost by
resynthesize amino acids
All five enzymes of the urea cycle have
potential defects that lead to disease
states.
Key points 2
Urea Cycle
In liver; Generates Urea; Consumes ATP (energy)
Majority of nitrogen disposal in cell
Carbamoyl phosphate
Catalyzed by Carbamoyl phosphate synthase I
Incorporate first nitrogen; energy requiring
Citrulline
Formed from Carbamoyl phosphate and Ornithine
Catalyzed by Ornithine Transcarbamoylase
Transported from Mitochondria into Cytoplasm
Citrulline and Aspartic Acid (Asp) react
Asp is source of second nitrogen
Energy required in reaction
Urea Cycle and Citric Acid Cycle use common reactions
Blood Urea Nitrogen is measure of Blood Urea Level
Ornithine Transcarbamoylase Deficiency
High ammonia in blood (hyperammonemia), low to no detectable
citrulline and high orotate
Amino Acid Synthesis
Emphasis on
Inborn errors of metabolism generating
disorders
Cofactors
Amino Acid Metabolism
Absorption Transport
=
1 (Dr Albritton)
4 Glycoge
n and (3, 4, 5: Amino Acids 2 and 3
Fatty
Acids 3
(Storage
)
Essential and Non-Essential Amino
Acids
Some caveats:
Supplemental Arginine is sometimes required under conditions of
growth pregnancy and children.
Cysteine and Tyrosine synthesis depends on adequate amounts of
essential amino acids Met (i.e., sulfur) and Phe, respectively.
The 11 non-essential amino acids can be
synthesized
The 11 non-essential amino acids can be
synthesized
The 11 non-essential amino acids can be
synthesized
Urea Cycle
*
*Precursor to ornithine
Synthesis of Tyrosine (Degradation of
Phenylalanine)
Synthesis of Tyrosine (Degradation of
Phenylalanine)
Phenylalanine is an essential
amino acid and obtained
through the diet
Figure 39.15
Phenylalanine is an essential
amino acid and obtained
through the diet
Figure 39.16
Continued:
A block in Tryosine Aminotransferase generates
increased levels of Tyr and results in a disorder
called Tyrosinemia II
Figure 39.5
Tetrahydrofolate (FH4) is the reduced
form of Folic Acid (Folate)
FH4 is a cofactor
involved in transferring
one-carbon groups
One carbon groups
(~methyl) attached to
folate are called the one-
carbon pool
Folate is involved in
glycine synthesis,
nucleotide metabolism
and transfer of carbon
to vitamin B12.
Tetrahydrofolate (FH4) is the reduced
form of Folic Acid (Folate)
Folate and derivatives
are obtained from
green leafy vegetables,
fruits and legumes
Reduced form (FH4) is
most common form in
body
Dietary folate is
reduced
So FH4 or FH2
Supplemental folate is
oxidized
Folate and Fetal Neural Tube
Defects
Folate deficiency during pregnancy has been
associated with an increased risk of neural tube
defect in the developing fetus and spina bifida.
Folate deficiency causes inhibition of DNA
synthesis leads to neural tube defects.
First observed in women with variant enzyme in
folate metabolism
Recommendation is that women considering
getting pregnant begin taking folate
supplements before conception and during at
least 1 month after conception
USDA has mandated that folate be added to
flour-containing products
Cysteine can be made from Serine and
Methionine (via S-Adenosylmethionine;
SAM)
Cysteine can be made from Serine and
Methionine (via S-Adenosylmethionine;
SAM)
Vitamin B12
Also called cobalamin
Coordinates cobalt
Vitamin B12 is obtained
from meat, eggs, dairy,
fish, poultry and seafood
Cofactor for two
reactions
Transfer of methyl group
from FH4 to Homocysteine
to form Methionine
[Rearrangement of
methylmalonyl-CoA to
generate succinyl-CoA]
FH4, Vitamin B12 and S-
Adenosylmethionine are methyl donors.
S-Adenosylmethionine (SAM) is
generated from Met and ATP
Note: Methionine is essential and obtained from diet.
SAM donates a methyl group (similar to FH 4)
which produces SAH, then Homocysteine
Note: Methionine is essential and obtained from diet.
FH4 can transfer a methyl group to Vitamin
B12
Homocysteine can accept a methyl group
from Vitamin B12 to regenerate Methionine
Alternatively: Homocysteine (derived from Met)
and Serine react to generate an intermediate,
which is cleaved to generate Cysteine
=intermediate
Metabolic Disorder of Cysteine
Synthesis
Homocysteinemia = High
homocysteine in blood
Homocysteinemia describes a biochemical
abnormality
Can result from deficiency of several
molecules
results when
Cystathionine -synthase (CBS) is
defective.
CBS is the enzyme that produces the
You do not
intermediate. need to
know this
enzyme
name for
exam
=intermediate
Homocysteine
can form
Homocystine
=intermediate
Homocysteinemia
Pathology is highly variable but can
include
Mental retardation (50%)
Dislocated optic lenses (80%), usually
downward
High levels of Homocysteine and Met interfere
with collagen function
Differs from that observed in Marfans syndrome
Abnormal blood clotting
Tissues have infarcts (lack of oxygen)
Osteoporosis, lengthening of long bones
1. Diet low in Methionine
2. Oral Vitamin B6 (precursor to PLP; cofactor
of CBS)
unknown mechanism; works in 50% of
CBS mutants
=intermediate
The 11 non-essential amino acids can be
synthesized