Nucleotides: Synthesis and Degradation

Nitrogenous Bases
Planar, aromatic, and heterocyclic Derived from purine or pyrimidine Numbering of bases is unprimed

Nucleic Acid Bases

Purines Pyrimidines

Sugars
Pentoses (5-C sugars) Numbering of sugars is primed

Sugars
D-Ribose and 2-Deoxyribose

*Lacks a 2-OH group

Nucleosides
Result from linking one of the sugars with a purine or pyrimidine base through an Nglycosidic linkage
Purines bond to the C1 carbon of the sugar at their N9 atoms Pyrimidines bond to the C1 carbon of the sugar at their N1 atoms

Nucleosides

Phosphate Groups
Mono-, di- or triphosphates Phosphates can be bonded to either C3 or C5 atoms of the sugar

Nucleotides
Result from linking one or more phosphates with a nucleoside onto the 5 end of the molecule through esterification

Nucleotides
RNA (ribonucleic acid) is a polymer of ribonucleotides DNA (deoxyribonucleic acid) is a polymer of deoxyribonucleotides Both deoxy- and ribonucleotides contain Adenine, Guanine and Cytosine
Ribonucleotides contain Uracil Deoxyribonucleotides contain Thymine

Nucleotides
Monomers for nucleic acid polymers Nucleoside Triphosphates are important energy carriers (ATP, GTP) Important components of coenzymes
FAD, NAD+ and Coenzyme A

Naming Conventions
Nucleosides:
Purine nucleosides end in -sine
Adenosine, Guanosine

Pyrimidine nucleosides end in -dine

Thymidine, Cytidine, Uridine

Nucleotides:
Start with the nucleoside name from above and add mono-, di-, or triphosphate
Adenosine Monophosphate, Cytidine Triphosphate, Deoxythymidine Diphosphate

In-Class Activities
Look at the Nucleotide Structures Take the Nucleotide Identification Quiz Be prepared to identify some of these structures on an exam. Learn some tricks that help you to distinguish among the different structures

Nucleotide Metabolism
PURINE RIBONUCLEOTIDES: formed de novo
i.e., purines are not initially synthesized as free bases First purine derivative formed is Inosine Monophosphate (IMP)
The purine base is hypoxanthine AMP and GMP are formed from IMP

Purine Nucleotides
Get broken down into Uric Acid (a purine) Buchanan (mid 1900s) showed where purine ring components came from:

N1: Aspartate Amine C2, C8: Formate N3, N9: Glutamine C4, C5, N7: Glycine C6: Bicarbonate Ion

Purine Nucleotide Synthesis

COO

O C

OOC
2-

O3P O CH2 H H

O H

H OH

C4 C H2N
5

N CH N

Aspartate + ATP

ADP + Pi

HC CH2 COO

N H

C4 C H2N
5

N CH N

OH OH -D-Ribose-5-Phosphate (R5P)
ATP
Ribose Phosphate Pyrophosphokinase

SAICAR Synthetase

Ribose-5-Phosphate Carboxyamidoimidazole Ribotide (CAIR)

AIR Car boxylase ADP + Pi

Ribose-5-Phosphate 5-Aminoimidazole-4-(N-succinylocarboxamide) ribotide (SAICAR)

Fumarate
Adenylosuccinate Lyase

AMP

ATP +HCO3

O C

2-

O3P O CH2 H H OH

O H OH

H O

O P O O

O P O O

HC 4 C H2N
5

N CH N
H2N

C4 C H2N
5

N CH N

Ribose-5-Phosphate
5-Phosphoribosyl--pyrophosphate (PRPP)

Ribose-5-Phosphate 5-Aminoimidazole-4-carboxamide ribotide (AICAR)

N10-FormylTHF

5-Aminoimidazole Ribotide (AIR)

ADP + Pi AIR Synthetase ATP

Glutamine + H2O Amidophosphoribosyl

Transferase

Glutamate + PPi

H N H2C CH O NH
O C H

O C H2N

AICAR Transformylase

THF

2-

O3P O CH2 H H OH

O H

NH2

C4 C NH
5

N CH N

C HN

H OH

-5-Phosphoribosylamine (PRA)
Glycine + ATP
GAR Synthetase

Ribose-5-Phosphate Formylglycinamidine ribotide (FGAM)

FGAM Synthetase ADP + Glutamate + Pi ATP + Glutamine + H2O

Ribose-5-Phosphate 5-Formaminoimidazole-4-carboxamide ribotide (FAICAR)

H2O
IMP Cyclohydrolase

ADP + Pi

H 2C O
2-

NH2

H N H2C C
N10-Formyl-THF THF

O C N
4

CH O NH
2-

HN HC N
O3P O CH2 H H OH O

C NH H H OH
GAR Transformylase

CH N
H H OH

C5

O3P O CH2 H H OH

Ribose-5-Phosphate Formylglycinamide ribotide (FGAR)

Glycinamide Ribotide (GAR)

Inosine Monophosphate (IMP)

Purine Nucleotide Synthesis

at a Glance
ATP is involved in 6 steps PRPP in the first step of Purine synthesis is also a precursor for Pyrimidine Synthesis, His and Trp synthesis
Role of ATP in first step is unique group transfer rather than coupling

In second step, C1 notation changes from to (anomers specifying OH positioning on C1 with respect to C4 group) In step 2, PPi is hydrolyzed to 2Pi (irreversible, committing step)

Coupling of Reactions
Hydrolyzing a phosphate from ATP is relatively easy
G= -30.5 kJ/mol If endergonic reaction released energy into cell as heat energy, wouldnt be useful Must be coupled to an exergonic reaction

When ATP is a reactant:

Part of the ATP can be transferred to an acceptor: Pi, PPi, adenyl, or adenosinyl group ATP hydrolysis can drive an otherwise unfavorable reaction (synthetase; energase)

Purine Biosynthetic Pathway

Channeling of some reactions on pathway organizes and controls processing of substrates to products in each step
Increases overall rate of pathway and protects intermediates from degradation

In animals, IMP synthesis pathway shows channeling at:

Reactions 3, 4, 6 Reactions 7, 8 Reactions 10, 11

In Class Activity ***

Calculate how many ATP equivalents are needed for the de novo synthesize IMP. Assume that all of the substrates (R5P, glutamine, etc) are available

Note: You should be able to do this calculation for the synthesis of any of the nucleoside monophosphates

IMP Conversion to AMP

IMP Conversion to GMP

Regulatory Control of Purine Nucleotide Biosynthesis

GTP is involved in AMP synthesis and ATP is involved in GMP synthesis (reciprocal control of production) PRPP is a biosynthetically central molecule (why?)
ADP/GDP levels negative feedback on Ribose Phosphate Pyrophosphokinase Amidophosphoribosyl transferase is activated by PRPP levels APRT activity has negative feedback at two sites
ATP, ADP, AMP bound at one site GTP,GDP AND GMP bound at the other site

Rate of AMP production increases with increasing concentrations of GTP; rate of GMP production increases with increasing concentrations of ATP

Regulatory Control of Purine Biosynthesis

Above the level of IMP production:
Independent control Synergistic control Feedforward activation by PRPP

Below level of IMP production

Reciprocal control

Total amounts of purine nucleotides controlled Relative amounts of ATP, GTP controlled

Purine Catabolism and Salvage

All purine degradation leads to uric acid (but it might not stop there) Ingested nucleic acids are degraded to nucleotides by pancreatic nucleases, and intestinal phosphodiesterases in the intestine Group-specific nucleotidases and non-specific phosphatases degrade nucleotides into nucleosides
Direct absorption of nucleosides Further degradation Nucleoside + H2O base + ribose (nucleosidase) Nucleoside + Pi base + r-1-phosphate (n. phosphorylase)
NOTE: MOST INGESTED NUCLEIC ACIDS ARE DEGRADED AND EXCRETED.

Intracellular Purine Catabolism

Nucleotides broken into nucleosides by action of 5-nucleotidase (hydrolysis reactions) Purine nucleoside phosphorylase (PNP)
Inosine Hypoxanthine Xanthosine Xanthine Guanosine Guanine Ribose-1-phosphate splits off
Can be isomerized to ribose-5-phosphate

Adenosine is deaminated to Inosine (ADA)

Intracellular Purine Catabolism

Xanthine is the point of convergence for the metabolism of the purine bases Xanthine Uric acid
Xanthine oxidase catalyzes two reactions

Purine ribonucleotide degradation pathway is same for purine deoxyribonucleotides

Adenosine Degradation

Xanthosine Degradation

Ribose sugar gets recycled (Ribose-1-Phosphate R-5-P ) can be incorporated into PRPP (efficiency) Hypoxanthine is converted to Xanthine by Xanthine Oxidase Guanine is converted to Xanthine by Guanine Deaminase Xanthine gets converted to Uric Acid by Xanthine Oxidase

Xanthine Oxidase
A homodimeric protein Contains electron transfer proteins
FAD Mo-pterin complex in +4 or +6 state Two 2Fe-2S clusters

Transfers electrons to O2 H2O2

H2O2 is toxic Disproportionated to H2O and O2 by catalase

THE PURINE NUCLEOTIDE CYCLE

AMP + H2O IMP + NH4+
(AMP Deaminase)

IMP + Aspartate + GTP AMP + Fumarate + GDP + Pi

(Adenylosuccinate Synthetase)

COMBINE THE TWO REACTIONS:

Aspartate + H2O + GTP Fumarate + GDP + Pi + NH4+

The overall result of combining reactions is deamination of Aspartate to Fumarate at the expense of a GTP

Purine Nucleotide Cycle ***

In-Class Question: Why is the purine nucleotide cycle important in muscle metabolism during a burst of activity?

Uric Acid Excretion

Humans excreted into urine as insoluble crystals Birds, terrestrial reptiles, some insects excrete insoluble crystals in paste form
Excess amino N converted to uric acid
(conserves water)

Others further modification :

Uric Acid Allantoin Allantoic Acid Urea Ammonia

Purine Salvage
Adenine phosphoribosyl transferase (APRT)

Adenine + PRPP AMP + PPi

Hypoxanthine-Guanine phosphoribosyl transferase (HGPRT)

Hypoxanthine + PRPP IMP + PPi Guanine + PRPP GMP + PPi

(NOTE: THESE ARE ALL REVERSIBLE REACTIONS)

AMP,IMP,GMP do not need to be resynthesized de novo !

A CASE STUDY : GOUT

A 45 YEAR OLD MAN AWOKE FROM SLEEP WITH A PAINFUL AND SWOLLEN RIGHT GREAT TOE. ON THE PREVIOUS NIGHT HE HAD EATEN A MEAL OF FRIED LIVER AND ONIONS, AFTER WHICH HE MET WITH HIS POKER GROUP AND DRANK A NUMBER OF BEERS. HE SAW HIS DOCTOR THAT MORNING, GOUTY ARTHRITIS WAS DIAGNOSED, AND SOME TESTS WERE ORDERED. HIS SERUM URIC ACID LEVEL WAS ELEVATED AT 8.0 mg/dL (NL < 7.0 mg/dL). THE MAN RECALLED THAT HIS FATHER AND HIS GRANDFATHER, BOTH OF WHOM WERE ALCOHOLICS, OFTEN COMPLAINED OF JOINT PAIN AND SWELLING IN THEIR FEET.

A CASE STUDY : GOUT

THE DOCTOR RECOMMENDED THAT THE MAN USE NSAIDS FOR PAIN AND SWELLING, INCREASE HIS FLUID INTAKE (BUT NOT WITH ALCOHOL) AND REST AND ELEVATE HIS FOOT. HE ALSO PRESCRIBED ALLOPURINOL. A FEW DAYS LATER THE CONDITION HAD RESOLVED AND ALLOPURINOL HAD BEEN STOPPED. A REPEAT URIC ACID LEVEL WAS OBTAINED (7.1 mg/dL). THE DOCTOR GAVE THE MAN SOME ADVICE REGARDING LIFE STYLE CHANGES.

Gout

Impaired excretion or overproduction of uric acid Uric acid crystals precipitate into joints (Gouty Arthritis), kidneys, ureters (stones) Lead impairs uric acid excretion lead poisoning from pewter drinking goblets

Fall of Roman Empire?

Xanthine oxidase inhibitors inhibit production of uric acid, and treat gout Allopurinol treatment hypoxanthine analog that binds to Xanthine Oxidase to decrease uric acid production

ALLOPURINOL IS A XANTHINE OXIDASE INHIBITOR

A SUBSTRATE ANALOG IS CONVERTED TO AN INHIBITOR, IN THIS CASE A SUICIDE-INHIBITOR

ALCOHOL CONSUMPTION AND GOUT

Choi HK, Atkinson K, Karlson EW et al. . 2004. Alcohol intake and risk of incident gout in men: a prospective study. Lancet 363: 1277-1281

Lesch-Nyhan Syndrome

A defect in production or activity of HGPRT

Causes increased level of Hypoxanthine and Guanine ( in degradation to uric acid) stimulates production of purine nucleotides (and thereby increases their degradation)

Also,PRPP accumulates

Causes gout-like symptoms, but also neurological symptoms spasticity, aggressiveness, self-mutilation First neuropsychiatric abnormality that was attributed to a single enzyme

Purine Autism
25%

of autistic patients may overproduce purines To diagnose, must test urine over 24 hours

Biochemical findings from this test disappear in adolescence Must obtain urine specimen in infancy, but its difficult to do!
Pink urine due to uric acid crystals may be seen in diapers

IN-CLASS QUESTION ***

IN von GIERKES DISEASE, OVERPRODUCTION OF URIC ACID OCCURS. THIS DISEASE IS CAUSED BY A DEFICIENCY OF GLUCOSE-6-PHOSPHATASE.
EXPLAIN THE BIOCHEMICAL EVENTS THAT LEAD TO INCREASED URIC ACID PRODUCTION? WHY DOES HYPOGLYCEMIA OCCUR IN THIS DISEASE? WHY IS THE LIVER ENLARGED?

Pyrimidine Ribonucleotide Synthesis

Uridine Monophosphate (UMP) is synthesized first

CTP is synthesized from UMP

Pyrimidine ring synthesis completed first; then attached to ribose-5phosphate

N1, C4, C5, C6 : Aspartate C2 : HCO3N3 : Glutamine amide Nitrogen

Pyrimidine Synthesis
O

2 ATP + HCO3- + Glutamine + H2O

2 ADP + Glutamate + Pi

C HN CH C N COO
O3P O CH2 H H OH OH O H H

Carbamoyl Phosphate Synthetase II

O
C

C HN CH C N H Orotate
Reduced Quinone

O
PRPP PPi
2-

NH2 O C O PO3-2

C O

Orotate Phosphoribosyl Transferase

COO

Orotidine-5'-monophosphate (OMP)

Carbamoyl Phosphate
Aspartate Aspartate Transcarbamoylase (ATCase)
Dihydroorotate Dehydrogenase

OMP Decarboxylase CO2

Pi

Quinone

O HO NH2 C O N H C CH2 CH COO

HN
H2O

O
HN

C CH CH N

C CH2 CH N H Dihydroorotate COO

2-

C O
O3P O CH2 H H OH OH O H H

C
Dihydroorotase

Carbamoyl Aspartate

Uridine Monophosphate (UMP)

UMP Synthesis Overview

2 ATPs needed: both used in first step

One transfers phosphate, the other is hydrolyzed to ADP and Pi

2 condensation rxns: form carbamoyl aspartate and dihydroorotate (intramolecular) Dihydroorotate dehydrogenase is an intramitochondrial enzyme; oxidizing power comes from quinone reduction Attachment of base to ribose ring is catalyzed by OPRT; PRPP provides ribose-5-P Channeling: enzymes 1, 2, and 3 on same chain; 5 and 6 on same chain
PPi splits off PRPP irreversible

OMP DECARBOXYLASE : THE MOST CATALYTICALLY PROFICIENT ENZYME

FINAL REACTION OF PYRIMIDINE PATHWAY ANOTHER MECHANISM FOR DECARBOXYLATION A HIGH ENERGY CARBANION INTERMEDIATE NOT NEEDED NO COFACTORS NEEDED ! SOME OF THE BINDING ENERGY BETWEEN OMP AND THE ACTIVE SITE IS USED TO STABILIZE THE TRANSITION STATE
PREFERENTIAL TRANSITION STATE BINDING

UMP UTP and CTP

Nucleoside monophosphate kinase catalyzes transfer of Pi to UMP to form UDP; nucleoside diphosphate kinase catalyzes transfer of Pi from ATP to UDP to form UTP CTP formed from UTP via CTP Synthetase driven by ATP hydrolysis Glutamine provides amide nitrogen for C4 in animals

Regulatory Control of Pyrimidine Synthesis

Differs between bacteria and animals

Bacteria regulation at ATCase rxn

Animals regulation at carbamoyl phosphate synthetase II

UDP and UTP inhibit enzyme; ATP and PRPP activate it UMP and CMP competitively inhibit OMP Decarboxylase

*Purine synthesis inhibited by ADP and GDP at ribose phosphate pyrophosphokinase step, controlling level of PRPP also regulates pyrimidines

Orotic Aciduria

Caused by defect in protein chain with enzyme activities of last two steps of pyrimidine synthesis Increased excretion of orotic acid in urine Symptoms: retarded growth; severe anemia Only known inherited defect in this pathway (all others would be lethal to fetus) Treat with uridine/cytidine
IN-CLASS QUESTION: HOW DOES URIDINE AND CYTIDINE ADMINISTRATION WORK TO TREAT OROTIC ACIDURIA?

Degradation of Pyrimidines

CMP and UMP degraded to bases similarly to purines

Dephosphorylation Deamination Glycosidic bond cleavage

Uracil reduced in liver, forming alanine

Converted to malonyl-CoA fatty acid synthesis for energy metabolism

Deoxyribonucleotide Formation

Purine/Pyrimidine degradation are the same for ribonucleotides and deoxyribonucleotides

Biosynthetic pathways are only for ribonucleotide production Deoxyribonucleotides are synthesized from corresponding ribonucleotides

DNA vs. RNA: REVIEW

DNA composed of deoxyribonucleotides Ribose sugar in DNA lacks hydroxyl group at 2 Carbon Uracil doesnt (normally) appear in DNA
Thymine (5-methyluracil) appears instead

Formation of Deoxyribonucleotides

Reduction of 2 carbon done via a free radical mechanism catalyzed by Ribonucleotide Reductases
E. coli RNR reduces ribonucleoside diphosphates (NDPs) to deoxyribonucleoside diphosphates (dNDPs)

Two subunits: R1 and R2

A Heterotetramer: (R1)2 and (R2)2 in vitro

RIBONUCLEOTIDE REDUCTASE

R1 SUBUNIT
Three allosteric sites

Specificity Site Hexamerization site Activity Site

Five redox-active SH groups from cysteines

R2 SUBUNIT
Tyr 122 radical Binuclear Fe(III) complex

Ribonucleotide Reductase R2 Subunit

Fe prosthetic group binuclear, with each Fe octahedrally coordinated

During the overall process, a pair of SH groups provides the reducing equivalents
A protein disulfide group is formed Gets reduced by two other sulfhydryl gps of Cys residues in R1

Fes are bridged by O-2 and carboxyl gp of Glu 115 Tyr 122 is close to the Fe(III) complex stabilization of a tyrosyl free-radical

Chime Exercise
E. coli Ribonucleotide Reductase:
3R1R and 4R1R: R1 subunit 1RIB and 1AV8: R2 subunit Explore 1AV8: Ribonucleotide Reductase in detail.This is the R2 subunit of E. coli Ribonucleotide Reductase. The biological molecule consists of a heterotetramer of 2 R1 and two R2 chains. Identify the following structures:
8 long -helices in one unit of R2 Tyr 122 residue The binuclear Fe (III) complex The ligands of the Fe (III) complex

Mechanism of Ribonucleotide Reductase Reaction

Free Radical Involvement of multiple SH groups RR is left with a disulfide group that must be reduced to return to the original enzyme

RIBONUCLEOTIDE REDUCTASE

ACTIVITY IS RESPONSIVE TO LEVEL OF CELLULAR NUCLEOTIDES:

ATP ACTIVATES REDUCTION OF

CDP UDP INDUCES GDP REDUCTION INHIBITS REDUCTION OF CDP. UDP

dTTP

dATP INHIBITS REDUCTION OF ALL NUCLEOTIDES dGTP

STIMULATES ADP REDUCTION INHIBITS CDP,UDP,GDP REDUCTION

RIBONUCLEOTIDE REDUCTASE

CATALYTIC ACTIVITY VARIES WITH STATE OF OLIGOMERIZATION:

WHEN ATP, dATP, dGTP, dTTP BIND TO SPECIFICITY SITE OF R1 (CATALYTICALLY INACTIVE MONOMER)

CATALYTICALLY ACTIVE (R1)2 TETRAMER FORMATION (R1)4a (ACTIVE STATE) == (R1)4b (INACTIVE) CATALYTICALLY ACTIVE HEXAMERS (R1)6

WHEN dATP OR ATP BIND TO ACTIVITY SITE OF DIMERS

WHEN ATP BINDS TO HEXAMERIZATION SITE

Thioredoxin

Physiologic reducing agent of RNR Cys pair can swap H atoms with disulfide formed regenerate original enzyme
Thioredoxin gets oxidized to disulfide

Oxidized Thioredoxin gets reduced by NADPH ( final electron acceptor) mediated by thioredoxin reductase

Thymine Formation

Formed by methylating deoxyuridine monophosphate (dUMP) UTP is needed for RNA production, but dUTP not needed for DNA
If dUTP produced excessively, would cause substitution errors (dUTP for dTTP)

dUTP hydrolyzed by dUTPase (dUTP diphosphohydrolase) to dUMP methylated at C5 to form dTMP rephosphorylate to form dTTP

CHIME EXERCISE: dUTPase

1DUD: Deoxyuridine-5'-Nucleotide Hydrolase in a complex with a bound substrate analog, Deoxyuridine-5'-Diphosphate (dUDP). Explore dUTPase as follows:
Find the substrate in its binding site Find C5 on the Uracil group. Is there enough room to attach a methyl group to C5? Locate the ribose 2 C. What protein group sterically prevents an OH group from being attached to the 2 C atom? Find the H-bond donors and acceptors (to the uracil base) from the protein. What would be the effect on the H-bonding if the base was changed to cytosine?

Tetrahydrofolate (THF)

Methylation of dUMP catalyzed by thymidylate synthase

Cofactor: N5,N10-methylene THF

Oxidized to dihydrofolate

Only known rxn where net oxidation state of THF changes THF Regeneration:
reductase)

DHF + NADPH + H+ THF + NADP+ (enzyme: dihydrofolate

THF + Serine N5,N10-methylene-THF + Glycine
(enzyme: serine hydroxymethyl transferase)

REGENERATION OF N5,N10 METHYLENETETRAHYDROFOLATE

dUMP dTMP

thymidylate synthase

N5,N10 METHYLENE-THF

DHF

GLYCINE
serine hydroxymethyl transferase

NADPH + H+
dihydrofolate reductase

NADP+
THF

SERINE

INHIBITORS OF N5,N10 METHYLENETETRAHYDROFOLATE REGENERATION

dUMP dTMP

thymidylate synthase

N5,N10 METHYLENE-THF
X

DHF

GLYCINE
serine hydroxymethyl transferase

FdUMP

NADPH + H+
dihydrofolate reductase

NADP+
X

SERINE
THF

METHOTREXATE AMINOPTERIN TRIMETHOPRIM

Anti-Folate Drugs

Cancer cells consume dTMP quickly for DNA replication

Interfere with thymidylate synthase rxn to decrease dTMP production

(fluorodeoxyuridylate irreversible inhibitor) also affects rapidly growing normal cells (hair follicles, bone marrow, immune system, intestinal mucosa)

Dihydrofolate reductase step can be stopped competitively (DHF analogs)

Anti-Folates: Aminopterin, methotrexate, trimethoprim

ADENOSINE DEAMINASE DEFICIENCY

IN PURINE DEGRADATION, ADENOSINE INOSINE

ENZYME IS ADA

ADA DEFICIENCY RESULTS IN SCID

SEVERE COMBINED IMMUNODEFICIENCY

SELECTIVELY KILLS LYMPHOCYTES

BOTH B- AND T-CELLS MEDIATE MUCH OF IMMUNE RESPONSE

ALL KNOWN ADA MUTANTS STRUCTURALLY PERTURB ACTIVE SITE

Adenosine Deaminase
CHIME Exercise: 2ADA Enzyme catalyzing deamination of Adenosine to Inosine / barrel domain structure TIM Barrel central barrel structure with 8 twisted parallel -strands connected by 8 -helical loops Active site is at bottom of funnel-shaped pocket formed by loops Found in all glycolytic enzymes Found in proteins that bind and transport metabolites

ADA DEFICIENCY ***

IN-CLASS QUESTION: EXPLAIN THE BIOCHEMISTRY THAT RESULTS WHEN A PERSON HAS ADA DEFICIENCY (HINT: LYMPHOID TISSUE IS VERY ACTIVE IN DEOXYADENOSINE PHOSPHORYLATION)

ADA DEFICIENCY

ONE OF FIRST DISEASES TO BE TREATED WITH GENE THERAPY ADA GENE INSERTED INTO LYMPHOCYTES; THEN LYMPHOCYTES RETURNED TO PATIENT PEG-ADA TREATMENTS
ACTIVITY LASTS 1-2 WEEKS