Inborn Metabolism (Exam 1) Flashcards
pancreas
secretes insulin and glucagon in response to changes in blood glucose concentration
brain
transports ions to maintain membrane potential; integrates inputs from body and surroundings; sends signals to other organs
liver
processes fats, carbohydrates, proteins from diet, synthesizes and distributes lipids, ketone bodies, and glucose for other tissues; converts excess nitrogen to urea
portal vein
carries nutrients from intestines to liver
small intestine
absorbs nutrients from the diet, moves them into blood or lymphatic slides.
lymphatic system
carries lipids from intestine to liver
adipose tissue
synthesizes, stores, and mobilizes triacylglycerols
skeletal muscle
uses ATP to do mechanical work
what happens during strenuous exercise?
lactate builds up in the muscle
acidification of the muscle prevents what
continuous strenuous work
where is the lactase transported to?
liver and converted to glucose there
what does the cori cycle recycle?
NAD+ so glycolysis can continue
energy containing nutrients
carbohydrates, fats, proteins
energy depleted end products
CO2, H2O, NH3
cell macromolecules
proteins, polysaccharides, lipids, nucleic acid
precursor molecules
amnio acids, sugars, fatty acids, nitrogenous bases
muscle
ATP produced by glycolysis for rapid contraction
phsyiological significance of the cori cycle
prevents lactic acidosis in muscle under anaerobic conditions
production of ATP during muscle activity
hexokinase is for the
muscle and other tissues
glucose utilization
phosphorylation of glucose commits glucose for use by that cell
glucokinase is for the
liver
glucokinase has a high
Km and a high Vmax for glucose
a large accumulation of what is dangerous? what does it lead to?
ketone bodies
metabolic acidosis
in diabetes,
insulin does not function properly
glucose levels are insufficient for energy needs
fats are broken down to acetyl-CoA
ketogenesis produces ketone bodies
inborn errors of metabolism
disorders in which single gene defects cause clinically significant blocks in metabolic pathways
pathology in metabolic disorders
from accumulation of enzyme substrate behind a metabolic block
deficiency of a reaction product
first treatment strategy for metabolic disorders
enhance the reduced enzyme activity
absence of glucose 6 phosphate
key feature: seizure
pathways affected: glycogen storage
treatment: cornstarch, frequent feeding
muscle glycogen phosphorylase deficiency
key feature: muscle pain on exertion
pathway affected: glycogen storage in muscle
treatment: glucose plus decreased exertion
carnitine/acylcarnitine translocate deficiency
key feature: seizures
pathway affected: mitochondrial import of fatty acids
treatment: carnitine supplementation and feeding tube
mitochondrial HMG-CoA synthase deficiency
key feature: semi comatose, no ketones
pathway affected: synthesizes ketone precursor
treatment: frequent feeding
increase xanthine oxidase activity and ABCG2 deficiency
key feature: pain and swelling in the joints, usually in the big toe and foot
pathway affected: chronic heterogenous disorder of urate metabolism
treatment: allopurinol
PKU (phenylketonuria) patho
deficiency of the liver enzyme phenylalanine hydroxylase
prevents normal metabolization of phenylalanine
phenylalanine
cannot be synthesized by the body and must therefore be consumed in protein rich foods
PKU disorder
autosomal recessive disorder caused by mutations in the PAH gene
deficiency of the liver enzyme phenylalanine hydroxylate
what cannot be excreted from metabolism in PKU subjects
Phenylacetic acid
goes to the brain
PKU treatment
strictly controlled phenylalanine free diet up to the age of 14
small doses must be supplied
why is PKU diet only up to 14 years of age?
after this age, growth and development of the brain is not affected by high levels of phenylalanine in the body
glycogen phosphorylase
breaks glycogen to make glucose every 4 glucose units from a branch point
coenzyme for glycogen phosphorylase
pyridoxal phosphate
produces G1P
activation of glycogen synthase under
well fed state by G6P
activation occurs in both liver and muscle
what effects glycogen to G1P conversion in the liver
glucose, ATP and G6P
what effects G1P to glycogen conversion in the liver
G6P
Glycogen phosphorylase deficiency
skeletal muscle, normal liver enzyme
autosomal recessive
leads to myoglobinemia and myoglobinuria
Glycogen phosphorylase deficiency effects
cramps upon exercise
no rise in blood lactate after exercise
Newborn screening
neonates are screened for inborn errors of metabolism
How is newborn screening done?
most commonly, a capillary blood sample is taken by a heel prick and blotted onto absorbent paper
important consideration when discussing newborn screening
Newborns are not screened for all inborn errors of metabolism. Each state is different in the amount they screen for (NY = 57)
Human gene therapy
modifies the expression of a gene or to alter the biological properties of living cells for therapeutic use
most common gene therapy technique
place gene in a vector and introduce into an organism
issues with gene therapy
there is a lot of problems with delivery
how to control symptoms of common inborn errors
diet
symptoms of common inborn errors
developmental delays, weight loss, growth challenges, seizures, etc.
uric acid metabolism
end product of purine metabolism
xanthine oxidase catalyzes hypoxanthine to xanthine and uric acid
hyperuricemia
excessive production or inadequate excretion
gout is the most common
form of inflammatory joint disease in men aged above 40 years old
gout
chronic heterogenous disorder or urate metabolism
result of gout
deposition of monosodium urate crystals in the joints and soft tissues, with accompanying inflammation and degenerative consequences
HMG-CoA synthase deficiency
autosomal recessive inherited disorder of ketone body metabolism
episodes of decomposition (vomiting, lethargy, coma, etc)
HMG-CoA synthase deficiency, if untreated, can lead to
permanent brain damage and death
HMG-CoA pathways
forms ketone bodies through HMG-CoA lyase
forms mevalonate for cholesterol synthesis through HMG-CoA reductase
HMG-CoA
formed in the liver
cholesterol/ketone bodies
carnitine-acylcarnitine translocase deficiency most common and gene
most common is severe and happens in newborns
caused by mutations in SLC25A20 gene
disorder carnitine-acylcarnitine translocase deficiency causes
fatty acid oxidation disorder
issue in processing long chain fatty acids
Heinz bodies
clumps of damaged hemoglobin located on red blood cells
cross linked hemoglobin
G6PD class 1
enzyme deficiency with chronic non-spherocytic hemolytic anemia
G6PD class 2
severe enzyme deficiency, less than 10% of normal activity
G6PD class 3
moderate to mild enzyme deficiency, 10-60% normal activity
G6PD class 4
very mild or no enzyme deficiency, at least 60% normal activity
clinical features pop G6PDH deficiency
neonatal jaundice and acute hemolytic anemia
presence of Heinz bodies
what is diagnostic for G6PDH deficiency
presence of Heinz bodies
What is responsible for gout?
dysfunctional ABCG2
Allopurinol
inhibits xanthine oxidase
blocks the conversion of uric acid
overexertion
excessive production: high serum uric acid and urine uric acid
underexcretion
inadequate secretion: high serum uric acid, normal/low urine uric acid
Two isoforms of G6PD
545 aa - inactive
515 aa
Ketoneogenesis
when glycogen stores are depleted such as during fasting and in undiagnosed diabetics
Diabetics have high levels of
acetone in their blood –> fruity odor of breath
large accumulation of ketone bodies leads to
profound metabolic acidosis
Psychiologic ketogenesis of fasting and the adaptive ketosis in starvation
never progress to life threatening acidosis
acetoacetate decarboxylase
forms acetone by enzymatic cleavage of acetoacetate
PKU disorder prevents
normal metabolism of phenylalanine –> tyrosine (and BH4 cofactor)
PKU results in
accumulation of phenylalanine
untreated individuals with PKU give off a
musty odor and they excrete large amounts of phenylalanine in their urine
Phenylalanine build up in the body to toxic levels
causes mental retardation
converted to phenyl acetic acid
what are foods with high levels of phenylalanine
meat, fish, eggs, cheese, milk products legumes and bread
if not diagnosed early,
the individual will suffer severe and irreversible brain damage
