Amino Acid Metabolism Flashcards
protein storage
no storage for proteins designated for energy metaboism
breakdown of body proteins only in times of great need -> the last resort
Cachexia; mm wasting, lipolysis
input to amino acid pool
- the intracellular synthesis of non-essential aminoacids
- tissue proteins
- dietary as source of essentail aminoacids
out puts of amino acid pool
- biomolecules w/ special functions; biogenic amines, thyroid hormones, heme, purine/pyrimidines, NO, etc
- degradation to the;
- ammonia / urea
- carbon skeleton; alpha-ketoacid -> pyruvated, acetyl CoA
C skeletons produced by aa degradation can be…(3options)
- oxidized to CO2 and H2O
- converted to glucose (glucogenic aa)
- converted to ketone bodies (ketogenic aa)
the NH3 produced by aa degradation can be (3 options)
- excreted in urine
- converted to urea then excreted
- used in synthesis rxns
first step of protein degradation
transamination - removal of alpha amino grp, freely reversible,
Aminotransferases (also syn non-essential aa from alpha-keto acid precursors)
PLP - B6
aa -> alpha-keto acid
alpha-ketoglutarate +NH2 grp -> glutamate
ALT & AST
ALT - alanine aminotransferase
AST - aspartate aminotransferase
liver is rich in both, AST can be just from mm check creatinine to confirm
second step of protein degradation
oxidative deamination - removal of aa group from glutamate
Glutamate Dehydrogenase (mito, liver, kidney)
glu -> alpha-ketoglutarate +NH3 special bc uses both; NADP+ and NADPH depending on dir forward rxn: +ADP, - GTP reverse rxn: only when NH3 is high anapleoritc rxn - another way to add intermediates to TCA cycle
transhydrogenation in mitochondria
ancillary rxn
NADH + NADP+ -> NAD+ + NADPH
mito need NADPH to reduced to keep glutathione in its functional form
transdeamination
combined process of transamination and oxidative deamination
most aa lose their alpha-NH2 this way
Thr & Lys are not substrates for PLP req aminotransferases -> req diff methods
transamination and the malate aspartate shuttle
in mito/cytosol OAA aspartate = transamination by AST
where does ammonia come from?
aa deamination
deamination of asn to asp, and gln-> glu
gut bacteria
etc
prob with ammonia
toxic to CNS. not sure why
perhaps due to dec in alpha-ketoglutarate
how is ammonia kept low;
- transport as glutamine (gln), alanine (ala)
2. conversion to urea by the urea cyle of the liver
why is it that making too much glutamine could be bad
rxn Glutamine synthetase requires ATP
decreases available glutamate which is imp for the neurotransmitter GABA
gln is osmoticly active -> cause edema in the brain
Glutamin synthetase
deals w ammonia problem;
glutamate -> glutamine (25% all circulating aa)
req ATP
brain, mm, liver
(reverse dir; glutaminase in liver and kidney)
most imp reason for low blood NH2 ?
rapid removal by the liver and conversion to urea
overall rxn of urea synthesis
NH4 (imp source; ox deam of glu) \+ HCO3(fr CO2) \+3ATP \+ NH2 (asp) -> urea
4 ATP ; 1 urea 5 rxns (2mito, 3cyto
carbamoyl phosphate synthetase 1
1st step of urea cycle; rate lim step
formation of carbamoyl phosphate
fr; CO2 and free ammonia
req N-acetylglutamate as an allosteric activator
*CPS 2 was in pyrimidine synthesis
ornithine transcarboamoylase (OTC)
2nd rxn of urea cycle
formation of citrulline from ornithine and carbamoyl phosphate
* only X-linked enzyme *
argininosuccinate synthetase (ASS)
3rd rxn of urea cycle
citrullin + asp -> arginosuccinate
driven by; hydrolysis of 3rd ATP
asp from transamination of glu by AST
lyase (ASL)
4th rxn of urea cycle;
cleavage of arginosuccinate to:
arginine (retains the N)
+ fumarate (carbon skel)
(recal purine ring synthesis)
fumarte = link to TCA
arginase
5th rxn of urea cycle
form orthinine + urea via cleavage of argnine
virtually exclusive to liver
ornithine re-enters urea cycle
urea diffuses into cycle
two amino acids you don’t find in protein. why?
citrullin and ornithine
no codons
why no urea in kidney? what happens there?
kidney makes arginine (arg) from citrulline
so, can generate Arginine here (thus arg is not really an essential aa)
lacks arginase => no urea
liver and regulation of ammonia
- UC enzymes in periportal hepatocytes
glutaminase & GDH (generate NH3) there as well -> produce ammonia where it will be cleaned up into urea quickly - gln synthetase in perivenous hepatocytes (catch ammonia missed). Glu generated by reversal of GDH rx when NH3 is high
so little ammonia escapes into blood (due to this structure)
glutamine can escape, but thats ok
what happens to the fumarate?
converted to malate via fumarase
malate - enters mito, malate dehydrogenase converts it to OAA generating NADH
regulation of urea cycle
substrate conce
act of CPS 1 by N-acetyl glutamate made by NAG synthase
change in enzyme conc; long term increase 20-30 fold in starvation
defect in ornithine transcarbamolyase
most common def in urea cycle
X-linked recessive
lethargy -> coma - > death ; encephalopathy
tx of x-linked OTC
- severe protein restriction + supplementation w alpha-keto acid analogs of essental aa
- N-scavenging drugs; bind up non-essentail aa for excretion
- antibiotics - ammonia from bacteria
- supp w arg in some cases
CPS 1 and CPS 2
both make carbamoyl phosphate
1 urea cycle, mito of liver, N from NH3, req NAG
2. de novo pyrimidine syn, cyto all nuc cells, N fr glutamine
orotic aciduria
deficiency of OTC
due to increased syn of pyrimidine Orotic acid
OTC: CP + ornithine -> citrulline; OTC deficient, CP increaes and is used to make OA
the three enzyems that fix NH3 into organic molecules;
Glutamate dehydrogenase
Glutamine synthetase
Carbamoyl phosphate synthetase 1
2 aa solely ketogenic
leucine
lysine
C appear in aceytl/aceto acetyle CoA
4(5) both keto and glucogenic
tryptophan isoleucine tyrosine phenylalanine (threonine)
solely glucogenic
alanine and rest of amino acids
metabolized to one of the following TCA intermediates: pyruvate OAA fumarate succinyl CoA alpha-ketoglutarate
(then, converted to PEP, to glucose)
the branched amino acids
leucine (leu)
isoleucine (ile)
valine (val)
taken up preferentially by skel mm
inc glucocorticoids and catecholamines -> aa released form mm -> skel mm initiates metabolism of BCAA (has the 1 aminotransferase)
metabolism of BCAA generates
energy; ATP
glutamine
alanine
glucose
ala and gln also produced to carry ammonia
branched chain amino acid aminotransferase
1 in muscle, plentiful here not in the liver
generates alpha keto acids from leu val ile
branch chain alpha-keto acid dehydrogenase
muscle and liver
Coenzymes: TPP, CoA, lipoic acid, NAD, FAD)
like PDH and alpha-KGD, common E3, all generate NADH
also, like PDH, covalently reg; active if deP
inhibited by NADH
Maple syrup urine disease
definciency in BCKAD accumulation of BCKA and BCAA AR, mennonites encephalopathy missence E1 tx; dietary restriction of BCAA, balance thiamine tx, effective in rar leu most toxic of BCAA challenge; provid suff calories so don't force them into catabolism
leu BCAA metabolism
acetoacetate + acetyl CoA
so leu; ketogenic
biotin dependent carboxylation required
val BCAA metabolism
propionyl CoA -> succinyl CoA -> glucose
val: glucogenic
ile BCAA metabolism
acetyl CoA and proprionyl CoA
so both ketogenic and glucogenic
source of ala from muscle:
Muscle:
val/ile ->succinyl CoA -(TCA)-> OAA -PEPCK-> PEP ->
Pyruvate -(ALT)-> ala
glu -ALT-> alpha-KG
Liver:
ala transported to liver where glu and pyurvate form;
ALT; ala->pyruvate & alpha-KG -> glu
pyruvate can be used as substrate for gluconeogenesis
glucose-alanin intertissue cycle
mucle produces pyruvate from glc & BCAA -> ala
liver: ala -(transamination)> pyruvate -(gluconeogenesis)> glucose
source of gln sent out by mm
glu produced by transmaination rxn
BCAA -> BC alphaketo acids, while
alpha-KG -> glutamate
then glu -> gln via Glutamine sythetase
gln used by gut, liver, kidney
what happens to gln in gut
glutaminase; gln -> glu + NH3
glu -> citrulline -> arginine (in kidney only)
or
glu + pyruvate -> alpha-KG + ala (via ALT)
ala -> glucose (in liver + kidney)
what happens gln/glu in liver and kidney
glutaminase; gln -> glu + ammonia
GDH; glu -> alpha KG + ammonia
alpha-KG -> glucose
use of ammonia tissue dep; liver -> urea or gln
ammonia produced in kidney
used in excretion of H+ in acidosis
especially imp in ketoacidosis
remember use of ammonia tissue dep
which does the gut prefer KB or gln
KB, uses them of gln; sparing gln
gln goes to kidney and liver
what amino acids have a special metabolism scheme?
aromatic aa:
trp
phe & tyr
trp metabolism
an essential aa, keto&glucogenic
trp oxygenase, contains heme
ox cleavage of pyrrole ring = N-formylkurenine
hyrolytic removal -> kynurenine & formate
-> 3-hydroxykynurenine ->
3 Products
- alanine (glucogenic)
- quinolinate (-> NAD/NADP synthesis)
- acetoacetyl CoA (ketogenic)
kenurenine can be
- catabolized to alanine & acetyle CoA (primary pathway)
2. met to quinolinate (minor, but phys sig pathway)
quinolinate
from trp metabolism
quinolinate or niacin (frm diet) -> NAD & NADP
Hartnup disorder
AR
defect in intestinal and renal abosorption of trp
symptoms; similar to niacin def (pellagra)
NT serotonin made from trp via hydroxylation (THB) and decarboxylation (PLP)
metabolism of phe and tyr
phe & tyr - gluc and keto genic
Phenylalanine hydroxylase (liver)
- Tetrahydrobiopterin (THB / BH2) gets ox
- hydroxylates C4
phe (essential) -> tyr - Irreversible
complete def; Phenylketonuria (PKU)
phenylketonuria (PKU)
most common disease of enzyme deficiency Phenylalanine hydroxylase (phe->tyr) AR phenylpyruvate (ketone) appears in urine mousy musty odor trp-> melanin (light skin/hair) sev mental retaradation Tx; diet low in phe + tyr supp Phe = teratogen Hyperphenylalanemia -> could be a def in synth of BH4 too
BH4 / THB
Tetrahydrobiopterin (THB / BH4)
involved in met of phe & tyr
phenylalanin hydroxylase
gets ox
def in this, or inab to reduce dihydrobiopterin back to tetra -> hyperphenylalaninemia
degradation of tyr
noteworthy bc virtually every step has a known clinical conseq if enzyme is deficient;
focus on 2:
alcaptonuria
tyrosinemia 1
alcaptonuria
trp degradation prob, AR = historical 1st
def; Homogentisate oxidase
homogentisate accumulates ox to dark pigment-like polymer -> urine, bone, CT
joint destruction, deterioration of cardiac valves
glucogenic amino acids
all but leu and lys
