Quiz 8 Flashcards
what way can THF ox/red reactions go
methylene can go to methenyl OR methyl
methyl CANNOT be oxidized further
what AA can react with THF
serine+THF glycine + 3
what is the glutamic acid reaction
glutamate + NAD alphaKG + NADH+ NH3
how is glutamine produced
glutamate + NH3 + ATP –> Glutamine + ADP + Pi
*THIS is how we get ammonia from other cells to liver to it can undergo urea cycle
how is aspartate produced
transamination:
OAA –> Aspartate
Glutamate –> alphaKG
how is asparagine produced
Aspartate + glutamine + ATP –> Asparagine + glutamate + ADP + Pi
*GLUTAMATE can give aspartate and glutamine which can give asparagine
how is alanine produced
Amino transferase reaction
Pyruvate –> Alanine
Glutamate –> alphaKG
*exercising muscle is using a lot of glucose so lots of pyruvate being produced and exceeding capacity of PDH and LDH reactions. XS pyruvate converted to alanine, leaves muscle, goes to liver and gets converted back to pyruvate where it can undergo gluconeogenesis and then glucose can go back to muscle
what is the AA that cycles with gluc in exercising muscle
ALANINE. exercising muscle is using a lot of glucose so lots of pyruvate being produced and exceeding capacity of PDH and LDH reactions. XS pyruvate converted to alanine, leaves muscle, goes to liver and gets converted back to pyruvate where it can undergo gluconeogenesis and then glucose can go back to muscle
how is proline produced
glutamate –> gamma Glutamic semialdehyde –> ornithine and proline
what is ornithine produced from and what can it become
glutamate –> gamma glutamic semialdehude –> ornithine –> arginine (needs aspartate)
is arginine essential?
in adults, glutamate pathway is enough but in children it isnt so it is considered an essential AA
how is cysteine formed
methionine –> SAM –> SAH –> homocysteine + serine –> cysteine
*non essential as long as we have methionine and serine
how is tyrosine produced
phenylalanine –> tyrosine
how is serine produced
either from 3PGA in glycolysis or from reverse of folic acid reaction
glycine + THF –> serine (REVERSIBLE!)
how is glycine produced
glycine + THF –> Serine + methyleneN5N10THF
OR
de novo from CO2 + ammonia + methylene THF
(methylene can come from histidine or another serine)
what are catecholamines
DOPA, dopamine, norepi, epi
where are catecholamines synthesized
in brain as adrenals, function as neurotransmitters and regulators of blood flow, BP, metabolism, and E production
what is parkinsons caused by
deficiency in dopaminergic neurons in substantia nigra of brain. tx with DOPA which can cross BBB, while dopamine cannot
catecholamine path
tyrosine –> DOPA + DHB + H2O–>Dopamine –> Norepi –> Epi
dopa to dopamine
dopa decarboxilase with PLP (loses CO2)
dopamine to norepi
OH in, cofactor is vit C
norepi to epi
SAM, CH3 is put on
tyrosine to DOPA + DHB + H20
tyrosine hydroxylase, THB + O2
what is GSH produced from
3 Amino Acids (glutamate, cysteine, glycine)
Glutamate + cysteine + ATP –> glu-cys + glycine + ATP –> GSH
what can tryptophan produce (not in brain)
acetyl coA/NH4/CO2 via tryptophan deoxygenase
NOTE: some metabolites can produce NAD and NADP
what is pellagra caused by
deficiency in tryptophan
what does tryptophan metabolize to in the brain
5 hydroxytryptophan –> serotonin (neurotransmitter, vasoconstrictor, important for blood pressure) –> melatonin
how does serotonin become melatonin
SAM becomes SAH
how does 5HT become serotonin
decarbox with PLP as cofactor
how is creatine produced
glycine + arginine –> guanidoacetate + ornithine –> creatine
what can creatine produce
creatine +ATP –> creatine phosphate –> creatinine
what is important about creatine phosphate reaction
reversible so it can produce ATP, one of the ways that our body stores ATP for muscle and brain. different isoforms in diff tissues so can be diagnostic for heart attack, stroke, etc
decarbox of glutamate gives
GABA - inhibitory neurotransmitter (PLP cofactor)
decarbox of histidine gives
histamine - vasodilator, allergic rxns, protein digestion (PLP cofactor)
decarbox of serine
ethanolamine (base in phospholipid phosphatidyl ethanolimine) PLP cofactor
decarbox of ornithine
putrescine (precursor to DNA binding polyamine spermine) PLP cofactor
how is nitric oxide produced
ariginine + oxygen –> nitric oxide
what is function of nitric oxide
vasodilator, regulates BP, prevents platelet aggregation. given after heart attacks
nitric oxide and bacteria
reacts with heme enzymes to block oxygen activation but also affects mammalian anzymes
what can aginine become
citrulline, ornithine, nitric oxide
what is heme important for
carrier for oxygen carrier proteins (hb), electron transfer enzymes (mito cytochomes), cyt p450 for drug metabolism
where is heme synthesized
mainly in liver and erythropoetic tissues but all do some. (initially in mito and then goes out to cytosol)
shape of heme
ring shaped with iron in the center
how is heme synthesized
- succinyl coA + glycine –> delta ALA - leaves matrix
- 2 ALA condense –> PBG
- PBG x 4 –> uroporphyrinogen III which decarboxylates to give coprophorinogen which decarboxylates to give protophorinogen (BACK TO MITO!)
- Protophyrinogen 9 oxidized to Protophyrin
- Protophyrin with ferrochelatase gives Heme
what steps of heme synthesis are inhibited by lead
- ALA dehydratase when two ALA condense to give PBG
2. Ferrochelatase with protophyrin becomes Heme
what is the RL step of heme synthesis
succinyl coA + glycine –> ALA (IN MATRIX!)
how is iron in blood carrier, how is iron in blood stored
carried as apotransferrin, stored as ferritin
what function does ferritin have
antioxidant, binds iron so it cant undergo fenton reaction
what are prophyrias
deficiencies in each of the enzymes in heme biosynthetic pathway result in accumulation of porphyrin substrates. MANY double bonds can be oxidized by ROS singlet O2
heme breakdown time
RBCs Hb every 120 days, cytochromes 10-20 days
heme breakdown pathway
heme –> bilverdin + CO –> bilirubin –> bilirubin albumin –> bilirubindiglucorinide (conjugated) –> bile –> urobilinogin (urine) and stercobilin
what causes jaundice
accumulation of bilirubin - can be caused by lack of conjugation enzymes or blockage of bile duct
*conjugated bilirubin excreted in bile
where in the heme breakdown pathway does it enter liver
bilirubin –> bilirubin albumin step
how is IMP synthesized
Ribose 5P from PPP —> PRPP
PRPP + glutamine —> 5 ribosyl 1 amine + glutamate
*catalyzed by amido phosphoribosyl transferase
THIS turns into IMP
what does IMP become
IMP + GTP + aspartate –> adenylosuccinate –> adenylate (AMP)
IMP + NAD –> xanthyalate —> Guanylate (gluatmine gives amino, becomes glutamate)
purine salvage pathway
RNA constantly being degraded - can be excreted as uric acid or salvaged
- Adenine phosphoribosyl transferase catalyzes: Adenine + PRPP –> AMP
- Hypoxanthine guanine phosphoribosyl transferase catalyzes:
hypoxanthine + PRPP —> IMP
guanine + PRPP –> GMP
what is lesch nyhan syndrom caused by
absence of hypoxanthine guanine phosphoribosyl transferase … makes IMP so can reproduce AMP and GMP
purine breakdown
GMP – guanosine – guanine – XANTHINE
AMP – IMP – inosine – hypoxanthine – XANTHINE
xanthine ultimately gets oxidized to uric acid which gets excreted
gout
XS uric acid forms - can inhibit xanthine oxidase (and therefore uric acid) with allopurinol
*colchicine and methotrexate block inflammatory reaction which is activated in response to high uric acid
how is UMP synthesized
glutamine + CO2 + 2 ATP —> carbamoyl phosphate –> orotic acid –> UMP
what is carbamoyl phosphate synthase used in
urea cycle and synthesis of pyrimidines
what is aspartates function in pyrimidine synthesis
reacts with carbamoyl phosphate to make orotic acid
what could high levels of orotic acid be caused by
decreased ornithine transcarbamylase in urea cycle so carbamoyl phosphate enters into pyrimidine synthesis pathway
how do you get from RNA to DNA
ribonucleotide diphosphate reacts with NADPH catalyzed by RR to give deoxyribonucleotide diphosphate
steps in RR
- ATP binds active site, signals to synthesize pyrimidines
- dCMP and dUMP formed, eventually dTTP formed.
- dTTP in binding site signals purines to be synthesized
- dGMP synthesized, eventually triggers dAMP which converts to dATP
- dATP in activity site shuts down enzyme
sites on RR
- active site where catalysis takes place, has thiol sites
- activity site
- substrate specificity site
SCIDS
due to deficiency of adenosine deaminsae, important in degradation of ATP to dATP to hypoxanthine and xanthine, get low b and T cells and low immune response
what would a test of high orotic acid in a newborn suggest
urea cycle deficiency
what does thioredoxin do
supplies necessary electrons to RR. in this process it gets oxidized, gets reduced back by thioredoxin reductase which gets its electrons via FADH2
glucogenic AA
produce pyruvate or any TCA cycle intermediate. All except leucine and somewhat lysine
ketogenic AA
produce Acetyl coA or acetoacetate. Leucine, Lysine, Isoleucine, Tryptophan, Phenylalanine, Tyrosine
C3 Family
5 OF THEM
Tryptophan Alanine Glycine Serine Cysteine
ALL GO TO PYRUVATE
“Try to get AL to take GLYstening SERiously for his CYS”
C4 family
2 OF THEM
Asparagine and aspartate
*Aspartate removed to OAA into cycle
C5 family
5 OF THEM
Histidine Proline Arginine Glutamine Glutamate
ALL GET TRANSFERRED TO alpha KG
HIS PROblems ARe that his is too GLUttonous (x2)
succinyl coA via AA
Valine
Isoleucine
Threonine
Methionine
All go to succinyl CoA
VAL IS only THREe and does METh which SUCks
rxn: methionine - homocysteine - alphaKB- propionyl coA - methylmalonyl coA - succinyl coA
branched AA breakdown
valine, isoleucine, leucine
transamination to alpha keto acid, oxidative decarboxylation to produce CO2 and acyle coA product
leucine breakdown
acyl coA from leucine only to acetyl coA and acetoacetate, ONLY KETOGENIC
valine and isoleucine breakdown
goes to propionyl coA to methylmalonyl coA to succinyl coA so GLUCOGENIC
isoleucine can also produce acetyl coA so also ketogenic
maple syrup urine disease
acyl coA dehydrogenase doesnt work so get build up of alpha keto acids which make urine smell like maple syrup
what happens to phenylalanine during breakdown
turns into tyrosine + DHB which can turn into fumarate or acetoacetate – ketogenic and glucogenic
what happens if you are mussing phenylalanine hydroxylase
phenylketonuria because phenylalanine accumulates and enters other side pathways it normally wouldnt enter
what could cause black urine
tyrosine metabolism issue - accumulation of homogenestic acid which usually goes to fumarate
what are ways we can treat inborn errors of metabolism
- Restrict substrate
- Provide cofactors
- Provide product
- Replace enzyme
- Provide alternate routes of elimination
- Treat secondary effects
PKU
Phenylketonuria - happens when there is a backup of phenylalanine because it cant become tyrosine –> dopamine –> melanin
what is the enzyme affected in PKU
phenylalanine hydroxylase with cofactor of tetrahydrobiopterin
how to treat PKU
restrict substrate – diet with no phenylalanine.
ADD tyrosine
- Can also give cofactor now
- can also replace enzyme now – clinical trials underway right now
outcome of treated PKU
PKU used to only be treated for 6 years of life - now have treatment for life
maternal PKU outcome
microcephaly, congenital heart disease, craniofacial abnormalities, small for gestational age
cofactor metabolism in PKU
tetrahydrobiopterin deficiency. Increased phenylalanine, decreased dopamine and serotonin because also involved in tyrosin and tryptophan metabolism
malignant PKU
when there is an issue with the cofactor. cant metabolize phenylalanine, tyrosine, OR tryptophan
organic acidemia
inborn error where pathway intermediate that is elevated is a non amino organic acid (no NH3)
organic acidemia labs
HIGH plasma ammonia
severe metabolic acidosis
acid metabolites in urine
metabolism of propionyl coA
propionyl coA carboxylase turns it into methylmalonyl coA. without this enzyme get back up!
*BIOTIN is cofactor
treatment of propionic acidemia
restrict substrate - VOMIT free formula
VOMIT = Valine, OCFA, methionine, isoleucine, threonine.
Provide biotin cofactor
Can give alternate path of elimination (carnitine can bind and eliminate propionic acid)
Treat secondary affects - ammonia detox and add bicarb to neutralize the acid
OTC deficiency
deficient in urea cycle - carbamoyl phosphate will go to pyrimidine synthesis. Ammonia will be extremely elevated
OTC treatment
only essential AAs, provide product of citruline, replace the enzyme with a liver transplant, dialysis to remove ammonia + ammonia scavenging meds
galactosemia
missing uridyl transferase - cant get from galactose 1 P to glucose 1P
tx of galactosemia
restrict substrate (no lactose or galactose),
GSD1
glycogen storage disease - glucose will be very low, lactate elevated, triglycerides elevated, uric acid elevated. blood sugars fall VERY fast after short fast
enzyme in GSD1
G6Phosphatase - cant regenerate glucose
medium chain acyl coA dehydrogenase deficiency (MCAD)
cant oxidize medium chain fatty acids, usually first manifestation is sudden death. fasting hypoketotic hypoglycemia because cant do beta ox of fatty acids
how to treat MCAD
avoid fasting, lower fat, higher carb diet. Add carnitine to bind and eliminate FA, treat secondary effects
Gauchers
accumulation of storage material in lysosomes - get erlenmeyere flask femur. ALL caused by mutations in B glucocerebrosidase. - cant make fatty acids which include plasma membrane sphingolipids
heteroplasmy and threshold effect
relevant in mitochondrial diseases as have all diff mit and only some will express issue.
replicative segregation
random allotment of daughter cells during cellular replication so some cells much more affected than others - some body parts more affected than others
