when does amino acid catabolism occur?
when aa are in excess, in positive nitrogen balance, and you're taking in more protein than need to replace body protein or make compounds
once body has enough aa to synthesize new protein & make nitrogenous molecules, start breaking down excess aa in diet
how are aa removed from the body
only via break down to other products, as there's no storage form of aa
what tissues degrade excess aa?
all tissues, but especially liver and muscle
what do aa break down become?
TCA cycle intermediates- OAA, aKG, succinyl CoA, fumarate
amino groups become urea
what are glucogeninc aa?
amino acids that produce pyruvate or any of the 4 TCA cycle intermediates, OAA, succinyl CoA, fumarate, aKG
aka aa that break down to anything else
includes all aa except for leucine, and to a large extent lysine
what are ketogenic aa?
aas that produce acetyl CoA and acetoacetate
leucine, lysine, phenylalanine, tyrosine, isoleucine, tryptophan
which aa are both glucogenic and ketogenic?
phenylalanine, tyrosine, isoleucine, tryptophan
b/c when break down, produce either pyruvate or a TCA cycle intermediate as well as acetyl CoA or acetoacetate
what are the C3 family of aa? what do they break down to?
alanine, serine, glycine, cysteine, tryptophan
break down to pyruvate
how does alanine break down
becomes pyruvate via GPT transamination rxn:
Ala + aKG -> Pyr + GLUT
how does tryptophan break down
its side chain is released as alanine during break down
how does cysteine break down?
bio importances of this?
cysteine loses its SH group, eventually forming sulfate + pyruvate
sulfate is important in:
1. biochemical conjugation reactions w/ drugs
2. in interacting w/ estrogens (estradiol sufate)
3. formation of cell surface and joint biochemicals such as chondroitin and hyaluronic acid sulfates
how does glycine break down?
becomes serine via serine transhydroxymethylase rxn, and Ser -> Pyruvate
how does serine break down?
serine can be dehydrated to pyruvate by serine dehydratase
what are the C4 family of aa?
aspartate and asparagine
how is aspartate broken down?
Aspartate -> OAA via GOT transaminase reaction
how is asparagine broken down?
Asparagine -> aspartate + ammonia by asparaginase
usefulness of asparaginase?
besides breaking down asparagine -> ammonia + aspartate, used to treat some leukemias beacuse asparagine is the AA in lowest level in proteins, so if remove asparagine with asparaginase and hydrolyze it to aspartate, can deplete tumor cell of asparagine and stop it from rapidly growing and dividing
what aa are in the C5 family? what do they make?
glutamate, glutamine, histidine, proline, arginine
all metabolized to aKG
how are the c5 family aa broken down?
glutamine, histidine, proline, arginine are all converted to glutamate
glutamate is oxidized to aKG by glutamate DH reaction
how does glutamine get metabolized
glutamine is hydrolyzed to glutamate + NH3 by glutaminase
how is histidine metabolized
histidine's metabolized to N-formimino glutamic acid
formimino group is transferred to THF to produce N-formimino THF + glutamate
N-Formiminot THF is major source of C for foic acid pool
how is arginine metabolized
arginine is hydrolyzed to ornithine + urea by arinase
ornithine can produce glutamic semi-aldehyde, which -> glutamate
what aa make succinyl CoA?
Met, Val, Thr, Isol which -> propionyl CoA -> methylmalonyl CoA -> succinyl CoA
what happens to the succinyl CoA made from the succinyl CoA family of aa?
breaks down to propionyl CoA
propionyl CoA -> D methylmalonyl -> L methylmalonyl -> succinyl CoA via methylmalonyl CoA mutase rxn
what causes methylmalonyl aciduria?
inborn error of metabolism causing deficiency of the methylmalonyl CoA mutase or of B12 or of the deoxyadenosyl transferase
what are the branched chain aa?
what happens to them in their breakdown?
valine, isoleucine, leucine
1. transamination, which converts the aa to the respective alpha keto acid of that particular amino acid
2. alpha keto acid undergoes oxidative decarboxylation to produce CO2 and acyl CoA product
this is catalyzed by acyl CoA DH complex
DH complex uses CoA, NAD, FAD, lipoic acid
3. acyl COA is further metabolized
acyl CoA from valine or isoleucine -> propionyl CoA -> methylmalonyl COA
acyl CoA from leucine -> acetyl CoA & acetoacetate
what's acetoacetate's categorization?
ketogenic because becomes acetoacetate and acetyl CoA, ultimately
what causes maple syrup urine disease?
what happens as result?
deficiency of branch chain a-keto acid DH needed for breakdown of Val, Iso, Leu
causes accumulation of these aa (Valine, Isoleucine, Leucine), and of the alpha keto acids produced by the transamination reaction
these are toxic compounds to the developing nervous system and cause severe neuro disturbances, failure to thrive, coma, death w/in first 2 years of life
how to treat maple syrup urine disease?
limit branch chain aa in diet, easy b/c these are all essential aa
how does maple syrup urine disease get its name?
urine spells like maple syrupe when a-keto acids spill over into the urine
how is phenylalanine metabolized?
phenylalanine -> tyrosine by phenylalanine hydroxylase
this uses oxygen and THB as cofactor
this is a mixed function oxidation
THB is oxidized to DHB
function of THB in phenylalanine catabolism?
supplies the reducing equivalents to form the OH of tyrosine and water
it becomes oxidized to DHB
how is cofactor regenerated for phenylalanine catabolism?
THB is regenerated from DHB by NADPH + DHB reductase
what is a mixed function oxidation? when does it occur?
in phenylalanine -> tyrosine by phenylalanine hydroxylase, which uses oxygen and THB as cofactor, the 2 atoms of O go to different products:
1 atom of O from O2 is incorporated into tyrosine product
1 atom of O from O2 is incorporated into water
is Phe an essential aa? is Tyr?
Phe is essential
Tyr is non-essential, as it can be made from Phe
what causes phenylketonuria?
inborn error of metabolism caused by deficiency of phenylalanine hydroxylase, which converts phenylalanine -> tyrosine and in some rarer cases, deficiency of THB, the cofactor
phenylalanine thus accumulates, -> side pathways, produces phenylketones: phenylpyruvate, pheynacetate, and phenyllactate
these cause severe neurological disturbances, mental retardation, death by age 20-30 if not treated
incidience of phenylketonuria?
how can you treat PKU? what aa would you add to a diet developed to treat PKU?
limit phenylalanine intake
supplement tyrosine intake
how does tyrosine catabolism proceed?
tyrosine itself or tyrosine from phenylalanine -> fumarate and acetoacetate by this pathway:
1. tyrosine undergoes transamination, produces para-hydroxyphenylpyruvate
2. p-hydroxyphenylpyruvate -> homogentisic acid by p-hydroxyphenylpyruate hydroxylase, which require sVitamin C (ascorbic Acid)
this step is an oxidation, hydroxylation, decarboxylation and ring migration!
3. homogentisic acid oxidized to fumarylacetoacetate by homogentisic acid oxidase
how are tyrosine and phenylalanine both ketogenic and glucogenic?
phenylalanine -> tyrosine
and tyrosine -> fumarate, which is TCA cycle = glucogenic, and acetoacetate, which is ketone body = ketogenic
what causes alcaptonuria? how does it manfest?
deficiency in the enzyme homogentisic acid oxidase which oxidizes homogentisic acid to fumarylacetoacetate
homogentisic acid is excreted into the urine, which becomes black as homogentisic acid gets further oxidized
not severe disease, but assoc w/ severe arthritis
treatment for alcaptonuria?
decrease phenylalanine and tyrosine intake
how does tryptophan metabolism proceed?
broken to alanine, acetyl CoA, and ammonia
thus it's both ketogenic and glucogenic
why are phenylalanine or isoleucine considered both glucogenic and ketogenic aa?
because they can form both glucogenic and ketone body intermediates.
Phenylalanine -> fumarate which is a TCA cycle intermediate which -> gluconeogenesis, and
isoleucine -> propionyl CoA -> L/D methylmalonyl CoA -> succinyl CoA -> gluconeogenesis,
however phenylalanine also -> acetoacetate, which is a ketone body, and
isoleucine -> acetyl CoA which + acetoacetyal CoA -> HMG CoA -> acetoacetate.
why can't leuceine be used for glugoneogenesis?
because it is catabolized to HmG CoA which is a ketone body intermediate that becomes acetoacetate; it’s not broken down to an intermediate i.e. from the TCA cycle that can undergo gluconeogenesis
how would carbon atoms from an aa like alanine wind up in a newly synthesized FA like palmitate?
Carbon atoms from an aa like alanine could become part of a FA like palmitate because alanine -> pyruvate via GPT transamination reaction, and pyruvate -> acetyl CoA -> malonyl CoA ->->-> FA synthesis pathway -> palmitic acid
what are causes for PKU? how is it treated?
PKU is caused by a deficiency in phenylalanine hydroxylase, which converts phenylalanine -> tyrosine; this causes phenylalanine to accumulate and undergo side pathway reactions to phenylketones: phenylpyruvate, phenylacetate, and phenyllactate.
Presence of these compounds causes severe neurological disturbances, mental retardation, and death by age 20-30 if not treated.
This is treatable by restriction of phenylalanine in the diet, while supplementing tyrosine since tyrosine is a metabolic product of phenylalanine catabolism
what are casues for MSUD, how is it treated?
Maple Syrup Urine Disease is caused by deficiency of a branch chain a-keto acid DH needed for the breakdown of Val, Iso, or Leu.
This causes accumulation of Val, Iso, or Leu, and of a-keto acids produced by the transamination reactions they undergo.
These acids are toxic compounds to the developing nervous system and cause severe neurological disturbances, failure to thrive, coma, and death within the first 2 years of life.
This is treatable by limiting brach chain amino acid in the diet.
what is a mixed function oxidase?
is a reaction that uses O2, and splits the atoms of O to put each in a different product of the reaction.
In aa catabolism, this occurs with phenylalanine -> tyrosine by phenylalanine hydroxylase, in which 1 atom of O is incorporated into the tyrosine product and 1 atom of O is incorporated into water
what is alkaptonuria?
caused by a deficiency in homogentisic acid oxidase, which oxidizes homogentisic acid to fumarylacetoacetate.
Homogentisic acid’s excreted into the urine, and thus further oxidized, turning urine black