Biochem Lecture 33 (Amino Acids as Metabolic Precursors) Flashcards
What is the most common inborn error of metabolism? What, biochemically-speaking, causes it?
phenylketonuria (1:11,000)
a defect in the enzmye:
phenylalanine— phenylalanine hydroxylase—>Tyr
causes MR due to build-up of phenylalanine; also sequelae due to decr Tyr
What happens to excess phenylalanine?
some goes through it’s “minor fate” pathway forming phenylpyruvate (ketone) which is excreted in the urine
How do you tx PKU?
START EARLY!
limit dietary Phe intake; dietary supplementation of Tyr (which has now become an essential a.a.)
How would PKU affect pigmentation? Why?
Hypopigmentation expected; PKU decreases available Tyr which is a precursor to melanin
What co-factor is req’d for phenylalanine hydroxylase activity?
Tetrahydrobiopterin (BH4)
What are non-PKU causes of hyperphenylalanemias?
Generally speaking, errors in the metabolism of armoatic amino acids (e.g. Tyr, Trp and Phe)
Examples: mutations in enzymes that synthesize BH4, which is synth’d from GTP:
GTP cyclohydrase, dihydrobiopterin synthetase
mutation in the enzyme that re-reduces dihydrobiopterin (BH2) back to tetrahydrobiopterin (BH4):
dihydrobiopterin reductase
So we know Phe is hydroxylated to form Tyr, what are the fates of Tyr?
1) tissue protein synthesis
2) catecholamines
3) melanin synthesis
4) metabolism to form ATP (i.e. fumarate synthesis)
Which is worse: PKU or non-PKU biopterin enzyme-assoc’d hyperphenylalaninemias?
Non-PKU biopterin-related Hyperphenylalaninemias are worse because, in addition to working with phenylalanine hydroxylase to catalyze Phe—Tyr, BH4 is a cofactor require for synthesis of:
Tyr—>DOPA (—>melanin)
((also: DOPA—>dopamine—>NE—>epi))
Trp—>5-HT (5-hydroxytryptophan) (—>serotonin)
Why can’t you just give PKU kids Tyr supplements?
Phe allosterically inhibits Tyr—tyrosine hydroxylase—DOPA
This is one of the reasons why simply supplementing PKU pts’s diets w/ Tyr isn’t enough; you need to get the [Phe] down. The increased [Phe] also inhibits CNS development. (All the effects are not fully understood)
How is serotonin synthesized from 5-HT? What cofactor is req’d?
What does serotonin do?
5-hydroxytryptophan—decarboxylase—>serotonin
This decarboxylase requires Vit b6 (pyridoxal-P)
sertonin is needed for: pain perception, SMM contract, “behavior”; prozac (fluoxetine) = SSRI
How do you treat BH4 (tetrahydrobiopterin) deficiencies?
again, start early:
low Phe diet; (other diet mods they didn’t go into)
5-HT, DOPA, and Biopterin supplementation
Doesn’t work well, most likely b/c your cells don’t have transport mechanisms for these molecules =/
How is histamine formed and why are we talking about it in this lecture? What co-factor is req’d?
Histamine is in this lecture as another example of an a.a. serving as a metabolic precursor.
In this case His—decarboxylase—>Histamine
The decarboxylase requires vitamin B6 (pyridoxal-P).
It removes the acid part (-COOH), leaving just the amine part (-NH2)
What are some actions of Histamine?
- triggers HCl release in the stomach
- allergic/inflammatory rxns
(same histamine, different receptor types)
What is GABA?
What does it do?
How’s it made?
GABA stands for γ-amino butyric acid
It acts as an inhibitory neurotransmitter
This is another example of a decarboxylation (requiring pyridoxal-P/Vit B6) to make a neurotransmitter:
glutamate —decarboxylase—> GABA + CO2
What does nitric oxide (NO) do?
How is it made?
neurotransmitter, SMM relaxant, immune f(X).
a free-radical, so short-half life, so only acts locally
It is made by:
L-Arginine + O2—NO synthase—>L-citrulline +** NO**
Also: NADPH, H+ ——> NADP+
