L9 - Synthesis of AAs, purines, pyrimidines

origin of ring atoms

C CO2, N aspartate, NCC glycine, C formate x 2, N glutamine x 2

de novo synthesis begins with

PRPP

de novo synthesis 1

glutamine (N) + PRPP (C1) > 5PRSA + glutamate + PPi

de novo 2

4PRSA + glycine (C) + ATP > GAR + ADP + Pi

de novo steps 3-11

***overall: use glutamine asp fumarate folate HCO3- , ATP, 1C donors

**** energy expensive

PRPP > 5PRSA > GAR > FGAR > FGAM > AIR < N5CAIR > CAIR > SAICAR > AICAR > FAICAR > IMP

de novo step 3-5

GAR > FGAR > FGAM > AIR

uses folate, glutamine, ATP, makes H2O

ring closure

de novo steps 6-7

are 1 step un eukaryotes

AIR > N5-CAIR > CAIR

de novo steps 8-10

CAIR > SAICAR > AICAR > FAICAR

uses Asp, folate, ATP

makes fumarate

de novo step 11

FAICAR > IMP + H2O

first purine ring closure

IMP turns into ___ or ____ via ____ or _____.

XMP or adenylsuccinate;

IMP DHase + H2O + NAD+

ASStase + Asp + GTP

adenylosuccinate

turns into AMP via adenylosuccinate lyase, also makes fumarate

*structure

xanthylate XMP

turns into GMP via XMP-GluAmidoTransase, Gln, ATP

*structures

AMP formation

IMP + Asp + GTP + AdenylSStase > adenylosuccinate

adenylosuccinate + adenylosuccinate lyase > AMP

GMP formation

IMP + H2O + NAD+ + IMPDHase > XMP

XMP + Gln + ATP > GMP

IMP regulation by feedback inhibition

Ri5P > PRPP

• X by ADP

PRPP > 5PRsA = inhibited by main products

• X AMP, GMP, X IMP

5PRSA > IMP

IMP > adenylosuccinate > AMP inhibited by end product

• X AMP

IMP > XMP > GMP inhibited by end product

• X GMP

AMP and GMP push each other when they are inhibited

purine salvage pathway

HGPRT = free guanine and hypoxanthine (adenine deam product)

Adenosine PRsTransase = ( free adenine with PRPP > AMP + PPi)

HGPRT

hypoxanthine-guanine phosopribosyl transferase

cat. salvage of free guanine and hypoxanthine (deam product of adenine)

adenosine phosphoribosyl-transferase

cat. rxn of adenine + PRPP > AMP + PPi

lesch-nyhan syndrome

coord, brain, hostile, compulsive;

lack of hypoxanthine-guanine phosphoribosyltransferase activity

cant do purine salvage

ribonucleotide reductase

deoxyribonucleotide

ribo > deoxyribo

thioredoxin

deoxyribonucleotide

intmd. H-carrying protein

glutaredoxin

deoxyribonucleotide

transfers power from GSH > ribonucleotide reductase

thioredoxin reductase

deoxyribonucleotide

cat. red of ox. form of thioredoxin by NADPH

GMP purine degradation pathway

GMP + 5’nucleotidase > guanosine + Pi

guanosine + nucleosidase > guanine (base) + ribose

guanine + guanine deaminase > xanthine + NH3

AMP purine degradation pathway

AMP + 5’Ntdase > adenosine + Pi

adenosine + adenosine deaminase > inosine + NH3

inosine + nucleosidase > hypoxanthine + ribose

hypoxanthine + xanthine oxidase > xanthine + H2O2

if nucleosidase fails, _____ increases which blocks ______, causing lymphocyte failure

dATP;

reductases

xanthine oxidase

flavoprotein

degrades xanthine > uric acid + H2O2

what species secretes what? primates v birds v reptiles v others mammals?

primates birds reptiles excrete uric acid

most mammals secrete allantoin

allantoin conversion

uric acid + urate oxidase > allantoin;

causes gout if fais

gout

uric acid buildup / improper breakdown of N bases, no allantoin

joint pain, crystallization,

treated by allopurinol, inhibitor

how do you treat gout

allopurinol, inhibitor of xanthine oxidase

converted to oxypurinol, comp. inhibitor

important cofactors in 1C transfers

biotin (CO2)

tetrahydrofolate (oxidation)

S-adenosylmethionine (methyl)

biotin transfers

CO2

tetrahydrofolate transfers

oxidation states

SAM transfers

methyl groups

megaloblastic anemia

B12 deficiency

decline in mature blood cells, for megaloblasts (big baby cells)

replacement with macrocytes

depletion in N5N10methlyenetetrahydrofolate