BICH 411 Exam #4 polymenis NUCLEOTIDES

Nearly ALL cells can make nucleotides from scratch

why?

The negative charges make them cell-impermeable

pyrimidine synthesis

bicarbonte + NH4 -> add 2ATP-> carbamoyl phosphate + aspartate-> pyrimidine ring-> PRPP

from PRPP in pyrimidine synthesis you make??

UTP-> CTP to RNA

UTP-> TMP-> dCTP to DNA

carbamoyl phosphate synthetase 1 rxn equation

2ATP + HCO3 - + NH3 → 2ADP + Carbamoyl phosphate + Pi

carbamoyl phosphate synthetase 2 difference?

it occurs in the cytoplasm does the same thing

where is ammonia coming from in carbamoyl phosphate synthetase 2

glutamate-> amidotransferase domain-> thioester interm.-> glutamate to rls ammonia which will be picked up to make carbamoyl phosphate

carbamoyl phosphate attacked by asp->

aspartate transcarbamylase ATCase to make ureidosuccinate

once youve made ureidosuccinate you can make?

dihydroorotate

dihydroorotate (DHODH) is dependent on what

FMN dependent

becomes orotate once oxidized

dihydrooritate is in cytosol but goes into the matrix to do what?

comes into matrix and goes through enzyme CHOOH to be used as QH2 in matrix and becomes orotate in cytosol

ribose must be activated in what form to be used

PLPP form

5-phospho-D-ribose-1-diphosphate

DHODH can be used as

immunosuppresents and chemotherapeutics

to make UMP

last step what happens

OMP decarboxylase must decarboxylate

generate carbanion

makes UMP

UMP to UTP?

UMP kinase, nucleotide diphosphate kinase

2ATP-> 2ADP

incorporated into RNA

UMP to CTP

UMP kinase, nucleotide diphosphate kinase, CTP synthetase-> CTP

2ATP-> 2ADP

glutamine-> glutamate

UMP to CTP requires

cytosine and uracil

source of amino group is glutamine

ready to make RNA and DNA (only if in deoxy form)

what happens if you don't have CTP synthase?

cannot make the full amount of CTP needed for making DNA-> cells in the process of replication but not fully replicated

make ------ nucleotides first before you can make ------- nucleotides

ribonucleotides before deoxyribonucleotides

ribonucleotides catalyzed by ----- to becomes deoxynucleotide-> dNTP

RNR

ribonucleotide reductase

where is the T found in dNTP?

its from U

dUMP->(thymidylate synthase adds methyl)-> dTMP

pyrimidine salvage does not mean

and an example

transport from the outside

Ureidosuccinate uptake is NOT salvage

cell doesn't need ----- and ------ but they can take them and use them

this is pyrimidine salvage

cytidine and uridine

very common pyrimidine salvage

uracil

extremely commonly used chemotherapy drug=

5-fluorouracil

5-fluorouracil aka 5-FU

how does it work?

incoorporated in UMP and is phosphorylated

(5-FUDP) UMP-> UMP kinase, nucleotide diphosphate kinase-> UTP

what is D5FUMP?

blocks thymidilate synthase (suicide inhibitor)

dUMP cannot be methylated and does not becomes dTMP

Methotrexate

-What is it?

blocks dihydrofolate from becoming tetrathydrofolate so that dUMP cannot be methylated and cannot become dTMP

other metabolic agents that act similar to D5FUMP?

Aciclovir, Cytarabine, AZT, Capecitabine, 5-Fluoroorotic Acid (5-FOA) and genetic selections

first thing you can make from purine before making ATP and GTP is?

IMP

Purine biosynthesis:

Building on ribose

purine salvage bases can be converted by:

GPRT, HPRT, APRT

pyrimidine breakdown/catabolism-> you can get

beta- alanine and some organisms urea

purine breakdown/catabolism->

primates, birds, reptiles and insects finish at->

uric acid in cycle

if too much uric acid you get?

GALT, effect of purine breakdown

xanthine oxidase ->

makes uric acid

blocking xanthine oxidase stops

what blocks it?

the making of uric acid

allopurinol

minimizes accumulation of uric acid

GALT=

uric acid crystals go to joints and cause inflammation

how to we make folate?

tetrahydrofolate THF cycle

Folate methyl transfers

folate biosynthesis starts with

a purine nucleotide and starts with GTP

chorismate is made as a key intermediate in?

tryptophan biosynthesis which feeds into the folate pathway

folate deficiency in pregnancy?

neural tube defects

yeast to the rescue!

folate fortified bread

another cofactor thats related as an input for synthesis of nucleotides is?

NAD+

how is NAD+ made?

some from tryptophan

AMP is also an input of the tryptophan synthesis

NAD and SIR2 can be used for

life span extension by calories restriction in saccharomyces cerevisiae

what are Sir2s?

increased silencing and longevity

from yeast

names for NAD compounds=

nicotinic acid Na

nicotinamide Nam

nicotinamide riboside NR

other enzymes along with Sir2 associated with longevity and silencing?

Hst 1, Hst 2, Hst 3

must be activated by NAD+