Heme Met + Purines/Pyrimidines

2 things heme is originally synth from

1. GLY

2. succinyl CoA

where is ALAS1 found?

non-hematopoietic cells

where is ALAS2 found?

hematopoietic cells

key reg enzye of heme synthesis

ALA-synthase

rxn catalyzed by ALA-synthase

succinyl CoA _ Gly → aminolevulinic acid

rxn cat by ALA-DH

aminolevulinic acid → porphobilinogen

what reg ALAS?

heme conc (increase in heme inhib ALAS)

increase in ALAS activity/expression __________ heme

increases

where is heme found?

• Hb

• CYP enzymes

how does drug induced porphyria occur?

increases ALAS which increases production of delta-aminolevulinic acid

what organs does heme travel thru?

spleen → liver → intestine → some goes to kidney

reg enzyme of heme degrad

heme oxygenase

s of heme oxygenase

heme + NAPDH

prod of heme oxygenase

biliverdin + Fe + CO + H2O + NADP+

s of biliverdin reductase

biliverdin + NADPH

prod of biliverdin reductase

bilirubin + NADP+

bilirubin

insol in water, so transported to liver by albumin

s of UDP glucoronyl transferase

bilirubin + 2UDP-glucoronic acid

prod of UDP glucoronyl transferase

bilirubin diglucuronide + UDP

jaundice

bilirubin leaks into BS as result of liver damage/bile secretion

what happens to bilirubin diglucuronide in intestine?

bacteria breakdown bilirubin diglucuronide → bilirubin → urobilinogen

• some is reabsorbed into blood → kidney for excretion (urobilinogen → urobilin)

what gives urine its color?

urobilin

what give feces its color?

stercobilin

most urobilinogen remains in _______ and bacteria convert it to _______

intestines / stercobilin

what induces heme oxygenase?

NO

• increases transcription

thymidine is only present in ______

DNA

what is NO synth from?

ARG

intermediate of purine synth

IMP

intermediate of pyrimidine synth

orotate

where does ribose-5-p for purine/pyr synth come from?

PRPP

where does most purine synth occur?

liver

enzyme of 1st committed step in purine synth

glutamine-phosphoribosyl aminotransferase

2 important feedback mech for purine synth reg

1. PRPP synthetase is inhib by ADP and GDP

2. Gln-phosphoribosyl aminotransferase is inhib by AMP, GMP, IMP

energy req for purine savlage

6 ATP

purine nucleoside phosphorylase

cat rxn where ribose-1-p is removed to rel a base → can be salvaged/degrad based on cell need

PRPP transferase

cat addition of ribose-5-p from PRPP to free base, gen a nucleotide

→ APRT, HGPRT

deaminase

removes removes an amine group from adenosine & AMP to form inosine & IMP

list order of enzymes in pyr synth

1. CPS II

2. ASP transcarbamoylase

3. Dihydroorotase

4. Dihydroorotate DH

5. Orotate Phosphoribosyl Transferase

6. Orotidylate Decarboxylate

7. Nucleotide Kinase

8. Cytidylate Synthetase

1st committed step of pyr synth

ASP transcarbamoylase

feedback inhib of pyr synth

UTP & CTP

s of CPSII

2ATP + bicarb + Glu (NH4)

prod of CPS II

carbamoyl phosphate + ASP

s of ASP transcarbamoylase

carbamoyl phosphate + ASP

prod of ASP transcarbamoylase

carbamoyl ASP

what enzyme converts dUMP to dTMP?

thymidylate synthase

what enzyme & pathway does methotrexate inhib?

dihydrofolate reductase

• involved in formation of THF to convert dUMP → dTMP

moa of methotrexate

cell death by inhib cell proliferation via thymidine synthase

what allosterically activates CPS II?

PRPP

what happens to purines that aren’t salvaged?

degraded to uric acid

degrad of purines

1. 5-nucleotidase removes phosphate

2. converts nucleoside to xanthine

3. xanthine oxidase converts xanthine → uric acid

product of xanthine oxidase

uric acid

rate-limiting step of purine degrad

xanthine oxidase

gout

accumulation of uric acid in BS due to decreased excretion → uric acid in bloodstream precipitates out as uric acid crystals in joints (esp feet)

what are pyrimidines degraded to?

urea