Nitrogen Metabolism - Kinde Flashcards
how to remove aa
becomes NH3 + carbon backbone partand oxidative deamination to wrea is the final step to N removal
carbon backbone part can be what
- Ketogenic : Acetyl CoA, Acetoacetate
2. Glucogenic : Pyruvate, TCA intermediates
the N giver and donor is what
Glutamate
glutamate + oxaloacetate —->
a-ketoglutoarate + Aspartate
glutamate + pyruvate —->
a-ketoglutoarate + Alanine
RLS in urea cycle
NH+4 —-> Carbamoyl Phosphate
* by carbamyl phosphate synthetase 1*
what happens after aa become glutamine
glu –> NH4 + Glutamine (glutamate dehydrogenase)
NH4 —-> Carbamoyl Phosphate
Carbamoyl Phosphate —-> UREA CYLCE
UREA CYCLE
Carbamoyl Phosphate + ornithine Citrulline Argininosuccinate Arginine Urea + Ornithine
10 essential aa
PVT TIM HALL
Phe, Val, Trp, Thr, Iso, Met, His, Rg, Leu, Lys
where does glutamine come from and how is is broken down
from extrahepatic tissue and brain
removes N from brain
and becomes glu by glutaminase
co factor for transaminases
PLP Pyridoxal phosphate
special thing about diseases caused by transporters that are defective
causes both X absorption in GI and X reabsorption in PCT of kidneys
2 transporter deficiency defects
- Hartnup = no neutral AAs (TRP)
2. Cystinuria = no dibasic AAs (Cystine dimer buildup)
what transporter is on the PCT for reabsorption on AAs
SLC (solute carrier) AAs and glucose enter with NA+
* on apical side** (facing environment)
which SLC is defected in Hartnup
SLC6A19 gene (TRYPTOPHAN transporter and other neutral AAs)
which SLC is defected in Cystinuria
SLC7A9 + SLC3A1 genes (dibasic AAs transporter)
which AAs are effected by Cystinuria
Cystine, Lys, Arg, Ornithine
what happens in WHAT to cause amminoaciduria
in Hartnup disease , inability to absorb or reabsorb
Ala, Asn, Ser, Thr, Tyr, Trp, Val, Leu, Ile, Phe, Gln
what happens if body cant have Trp (precursor for what)
it is the precursor for:
- Serotonin —-> Metatonin (MOOD, like anxiety, depression)
- Niacin —-> NAD + NADP (nystagmus, ataxia, photosensitivity, pellergra, hyperpigmentation)
how to Tx harnup disease
- niacin repletion by NICOTINIC ACID
- high protein diet, to get some AAs in
- VIT B3
what does Trp need besides the SLC6A19 to get reabsorbed or absorbed
VIT B6
how does Nicotinic acid treat hartnup disease
NA –> Nicotinamide (which spike Trp to make NAD de novo)
what does NAD help with in DNA
repair by binding to PARP enzymes
what happens in cystinuria
cystine is found as a dimer and cant get reabsorbed by dysfunctional transporter
COAL (dibasic AAs cant get into body) = Cys, Orn, Arg, Lys
Sx :and Tx: cystinuria
renal colic, abd pain from kidney stones of cystine crystals
Tx: alkaline diet (alkaline urine dissolves the crystals)
PKU has defective what in
primary
secondary
- Primary : phenylalanine Hydroxylase ( PHE –> TYR)
2. Secondary : dihydrobiopterin reductase (NADPH–> NADP+, cofactor) * not as severe
what does Tyr make
GLU and Melanin
another way of saying dihydrobiopterin reductase
BH4THB
what happens in PKU
Phe –> phenylpyruvate –> phenyllacetate + phenylacetate which are both toxic
since PHE cant become TYR
PKU Sx:
musty odor urine
—-I NTs to brain
severe brain dysfunction
PKU Tx:
- X Phe in diet
- supplement Tyr in diet
- supplement tetrahydrobiopterin
which disease do you always screen for in newborns
PKU (guthrie test)
Tetrahydrobiopterin + dihydrobiopterin is essential what
which is active
hydroxylation of aromatic AAs
by dihydrobiopterin reductase
also helps Trp make NE, E, S
- *** BH4 = THB is active
- *** qBH2 = DHB s inactive
Tyrosinemias all do what
have elevated Try (restricts TYR and PHE)
Transient Tyrosinemia
newborns dont have developed enzymes (4-HPPD) yet to breakdown Tyr = HIGH TYR
Tyrosinemia 1
cabbage like smell
X fumarylacetatoacetate hydrolase
= build up of succinylacetone = toxic for liver and kidney
= no heme + TCA + can need liver transplant
Tyrosinemia Tx
Nitisinone = 4-HPPD inhibitor
*prevents buildup of succinylacetone so NO LIVER PROBLEMS
= you still have excessive Tyr and Phe
Tyrosinemia 2
X tyrosine aminotransferase
= causes lesions on skin and cornea (tyr deposition)
mental problems
eye problems
Tyrosinemia 3
X 4 -HPPD : neurological problems (very rare)
buildup of tyrosine
Alkaptonuria
X homogenisate oxidase
= BLACK URINE, Bone, and sclera, arthritis
= accumulated homogentisic acid
Ammonia Toxicity happens due to
excessive NH4 (due to one of urea cycle enzymes not working)
= CNS and brain toxicity
** increased NH4
1.. causes a-keto +NH4 —-> glutamate (*opposite then favored)
2. HIGH glu + NH4 —-> glutamine
= low GLU
Ammonia Toxicity Sx
pH imbalance, astrocyte swelling in brain, cerebral edema, intracrainial HTN LOW GLU : 1. X GABA 2. low atp for brain * from high glutamine
Gout
Primary
secondary
high uric acid from PURINE metabolism deposited in joints
Primary = high uric acid production
secondary = cant excrete uric acid enough
what can increase chance of getting gout
beans, alcohol, meat, seafood, spinach, lentils
DM
gout Tx:
- limit purine
- Allopurinol —-I xanthine oxidase and makes purines soluble
- colchicine = decreases uric acid movement to joints
Acidemia
–> URAT1 transporter (reabsorbes uric acid)
normal excretion if uric acid
60%-70%
normal reabsorption of urate
90%
NAG synthase deficiency causes what
glutamate + Acetyl CoA –X–> NAG
HIGH Nitrogen accumulation (NH4)
= toxic to CNS and, V, coma, lethargy, no eating
what is the role of NAG
the cofactor to make NH4 —-> Carbomyl Phosphate
Hyperammonemia is what
one of the 6 enzymes of the urea cycle is defected or any of 2 transporters (Asp/Glu + ornithine)
Hyperammonemia by defected ornithine transcarboxylase (OTC)
- Carbomyl Phosphate cant leave mitochondria as Citrulline so it builds up and spills out into cytosol
- Carbomyl Phosphate in the cytosol is metabolized by pyrimidine synthase to OROTIC ACID —-CPS2—-> CMP in cytosol
- Orotic Acid becomes UMP eventully
= low BUN + hyperammonemia + orotic aciduria can happen
CPS2
first step of making pyrimidine de novo
stimulated by PRPP
inhibited by UTP
UMP synthase deficiency causes what
accumulation of orotic acid = orotic aciduria (since it can not continue on with pyrimidine de novo, so it accumulates)
OTC causes hyperammonemia because of what
the accumulation of CP leading to accumulated NH4+
OTC deficiency Tx: and also type of condition
X- linked
Protein in diet
UMP synthase deficiency Sx
orotic aciduria
NO low BUN or hyperammonemia
CSP 1 is found where and activated by what
mitochondria for urea cycle
NAG
CSP2 is found where and activated by what
Cytosol of Pyrimidine synthesis
PRPP
what leads to increased unconjugated bilirubin in infants
UDP-glucuronyl transferase deficiency
what can the UDP - glucuronyl transferase deficiency lead to besides jaundice
if mother takes Abs the baby cant metabolize drug and cant excrete unconjugated drug
= CHLORAMPHENICAL TOXICITY (Gray Baby Syndrome)
- circulatory collapse (low contractlity)
what drug to use if mother has an infection if baby has a UDP - glucuronyl transferase deficiency
Cephalosporins
conjugated vs inconjugated bilirubin
conjugated = soluble (is pink mixed with Diazo *can by assayed directly) unconjugated = insoluble (only with methanol is it soluble)
what removed bilirubin before birth and after
before : placenta
after : liver when mature enough
what can help jaundice in infants
blue fluorescent light makes unconjugated to conjugated bilirubin
pathologic reasons infants have jaundice
medication infection Hypoxia Hepatitis G6D X trauma
Physiologic reasons infants have jaundice
Low UGT enzyme
short RBC life
high bilirubin made
increased RBC mass circulation
