Chapter 32: Purine and Pyrimidine Metabolism I

Question 1

The 3 types of Pyrimidines are? Steps in synthesis?

Answer 1

Cytosine, Thymine and Uracil (1 RING)

“CUT the pyrimid(ine)”

Synthesis steps: 5

“a pyramid is a pentagon (5 sides)”

Question 2

The 2 types of purines are? Steps in synthesis?

Answer 2

Guanine, Adenine (2 RINGS)

“the GAP is PURe”

Synthesis steps: 10

Question 3

Metabolism and excretion of ___________ is not easy/problematic. Why?

Answer 3

Purines

Hard parts: toxic intermediates, the final product is uric acid.

Therefore, purine synthesis MUST be tightly regulated

Question 4

Where are nucleotides broken down for absorption? What enzymes break them down?

Answer 4

Small intestine: cells of the duodenum/jejunum contain enzymes to break down nucleotides for absorption

Enzymes: ribonucleases, deoxyribonucleases, nucleosidases, phosphatases

Question 5

Steps of nucleotide breakdown: First, ______ and _______ remove nucleotides from the phosphodiester backbone. Then, _________ remove a phosphate. Lastly, ____________ break down the nucleoside (no P) into pentose sugars and nitrogenous bases.

Answer 5

1. ribonucleases, deoxyribonucleases
2. phosphatases
3. nucleosidases

Question 6

Where do membrane transport proteins carry the products of nucleotide digestion (nitrogenous bases, P ion, pentose sugar)?

Answer 6

lumen —> epithelial cells (active/secondary active transport) —> interstitial fluid —> capillaries —> *LIVER & other tissues

Question 7

Nucleic acids are building blocks for …….

Answer 7

1. Electron carriers (FAD+, NAD+, NADP+)
2. CoA
3. cAMP: secondary messenger

Question 8

What is the MAIN precursor for ALL nucleotide synthesis (the “sugar”)?

Answer 8

***Phosphoribosyl pyrophosphate (PRPP): an “activated sugar molecule”

** IMPT: Used in both purine/pyrimidine synthesis and in salvage/de novo pathways

Question 9

The _______ pathway of nucleotide synthesis is used when we consume nitrogenous bases and use them as “building blocks”

Answer 9

SALVAGE PATHWAY: PRPP (activated ribose) + base = nucleotide

Question 10

The ________ pathway of nucleotide synthesis is used when there are not enough nitrogenous bases around and we must build nucleotides from scratch

Answer 10

DE NOVO PATHWAY: PRPP (activated ribose) + AA’s + ATP + CO2 + … = nucleotide

Question 11

What substrate is used to make PRPP via PRPP-synthetase? What kind of rxn occurs?

Answer 11

substrate: Ribose 5-phosphate (R5P)
enzyme: PRPP-synthetase —> adds 2 P’s (pyrophosphate) from ATP

Question 12

Where is Ribose 5-phosphate derived from?

Answer 12

Intermediate of the PPP and glycolysis

Question 13

How is PRPP controlled/regulated? Inhibitors/Activators?

Answer 13

Allosteric regulation

**Activated by: inorganic phosphate (Pi) and Mg2+ (cofactor)
**Inhibited by: ADP/GDP (low E states)

Question 14

What is the intermediate molecule of purine synthesis?

Answer 14

Inosine monophosphate

Question 15

What is the main organ that produces nucleic acids and manages ammonia, a key component in purine biosynthesis?

Answer 15

THE LIVER

Question 16

What is required for de-novo purine synthesis?

Answer 16

Glutamine, Aspartate, Glycine, CO2, formate

“FACe GaG”

Question 17

**IMPT
The first committed step in IMP production adds an amino group from GLUTAMINE to PRPP to form _______________? This is catalyzed by ___________.

Answer 17

product: 5-phosphoribosyl-1-amine

enzyme: PRPP Glutamine amidotransferase

leaving group: PPi (pyrophosphate)

Question 18

_____________ IS A COMMITTED PRODUCT FOR DE NOVO SYNTHESIS OR PURINES
*IMPT

Answer 18

PHOSPHORIBOSYLAMINE

Question 19

Number of steps from PRPP —> IMP?

Answer 19

11 steps (9 steps after formation of the committed molecule: phosphoribosylamine)

Question 20

What is an allosteric FEED-FORWARD activator of PRPP glutamine amidotransferase? Effect?

Answer 20

activator: PRPP
effect: increase in phosphoribosylamine (committed)/purine synthesis

Question 21

What are allosteric FEEDBACK inhibitors (end products) of PRPP glutamine amidotransferase? Effect?

Answer 21

feedback inhibitors: IMP, AMP, GMP
effect: decreased purine synthesis

Question 22

A pt with leukemia is put on ________________, a drug that inhibits PRPP glutamine amidotransferase. This works to block synthesis of _________.

Answer 22

drug: 6-mercaptopurine
blocks: synthesis of purines/DNA

Question 23

Once phosphoribosylamine is formed, glycine is added via ______________ and requires _________. This forms glycinamide ribotide (GAR) and begins the purine ring on ribose.

Answer 23

1. Glycinamide ribotide synthetase
2. ATP

Question 24

The biosynthesis of ______________ is done by attachment of enzymes that are grouped to form a channel that shuffles substrates/products through a tunnel. This is known as _____________. This strategy increases biosynthesis efficiency and prevents diffusion and degradation of unstable __________.

Answer 24

1. purines
2. channeling
3. intermediates

Question 25

Once Glycinamide ribotide (GAR) is formed, 2 reactions use charged ________ to deliver formyl groups to the structure. There is one C transfer with a carbonyl group at _____ and _______.

Answer 25

1. THF 2. C2, C8

Question 26

For the conversation of IMP to AMP, the carbonyl group is replaced by an amino group from ______________. This requires ________.

Answer 26

1. Aspartate 2. GTP

Question 27

For the synthesis of GMP from IMP, one H in the 2nd ring is replaced by an amino group from _________. This requires ______.

Answer 27

1. Glutamine 2. ATP

Question 28

In AMP synthesis, the carbonyl oxygen is first activated by using energy (GTP) and adding aspartate to make ________. The enzyme used in this rxn is ______________. Next, the carbon skeleton of aspartate is cut off, releasing _________ and forming AMP.

Answer 28

1. adenylosuccinate 2. Adenylosuccinate Synthetase 3. fumarate (leaving group)

Question 29

Adenylosuccinate Synthetase is activated by _________ and inhibited by ________.

Answer 29

1. GTP (high energy) 2. AMP (feedback inhibition)

Question 30

In GMP synthesis, IMP is first oxidized using _________ to form _______________. This reaction is coupled with the reduction of _____. Next, the carbonyl just created is activated by ATP and the enzyme _____________ transfers an amino group from glutamine.

Answer 30

1. IMP dehydrogenase 2. xantilate monophosphate (XMP) 3. NAD+ --> NADH 4. XMP-Gln amidotransferase

Question 31

In GMP synthesis, IMP dehydrogenase is inhibited by ______ and XMP-Gln aminotransferase is activated by ______.

Answer 31

1. GMP (feedback inhib) 2. ATP (need E for this rxn)

Question 32

AMP can be converted into ADP using ________. GMP can be converted into GDP using _____________.

Answer 32

1. adenylate kinase 2. guanylate kinase

Question 33

IMPT: The conversion of ALL nucleoside diphosphates (ADP, GDP into nucleoside triphosphates (ATP, GTP) is catalyzed by __________.

Answer 33

NDPK (nucleoside diphosphate kinase)

Question 34

N10-formyl tetrahydrofolate is made from the vitamin ______.

Answer 34

folate

Question 35

Sources of folate

Answer 35

Sources: ***leafy green vegetables, nuts and meats

Question 36

Folate is the precursor for formation of ________.

Answer 36

tetrahydrofolate (THF)

Question 37

What is required for all these processes?

Answer 37

THF (tetrahydrofolate)

Question 38

Folate can help to detoxify from ________ poisoning since it increases the metabolism of formic acid, a toxic byproduct.

Answer 38

methanol poisoning

Question 39

Who synthesizes folic acid by converting pteridine precursors and para-aminobenzoic acid into folic acid.

Answer 39

microorganisms

Question 40

Folic acid synthesis is inhibited by ________ antibiotics. These drugs inhibit bacterial synthesis of DHF/THF at the ______ incorporation step. Type of inhibition?

Answer 40

1. sulfonamide (sulfa drugs) 2. PABA 3. competitive inhibition (block the incorporation of PABA to form DHF)

Question 41

What enzyme converts folate --> dihydrofolate (DHF) --> tetrahydrofolate (THF). The same enzyme is used twice.

Answer 41

dihydrofolate reductase (DHFR) **it catalyzes the REGENERATION of THF

Question 42

What antibiotic inhibits DHFR?

Answer 42

1. trimethoprim **Trimethoprim's affinity for bacterial DHFR is several thousand times greater than its affinity for human DHFR.

Question 43

What carries activated 1-carbon units for biosynthetic pathways including amino acids and nucleotides?

Answer 43

tetrahydrofolate (THF)

Question 44

C1 units are covalently attached to THF at positions ____, _____ or both

Answer 44

N5, N10

Question 45

The C1 units from THF can be used..... 1. Directly as N5-N10-methylene-THF in the conversion of _____ to _____ via Thymidylate Synthase 2. It may be reduced to N5-methyl-THF for the synthesis of methionine from __________ via ____________. This enzyme requires _______. 3. it may be oxidized through N5-N10-methenyl-THF to N10-formyl-THF for use in ________.

Answer 45

1. dUMP; dTMP 2. homocysteine; homocysteine methyltransferase (methionine synthetase); vit B12 (cobalamin) 3. purine synthesis

Question 46

What can cause megaloblastic anemia in adults, cardiovascular dx or birth defects in infants?

Answer 46

FOLATE DEFICIENCY **in infants, it is treated by supplementing the diet with grains

Question 47

IMP biosynthesis is an energetically consuming process that requires the hydrolysis of how many ATPs?

Answer 47

SIX

Question 48

Origins of the various parts of a purine molecule?

Answer 48

C4, C5, N7: Glycine C2, C8 (via a formyl group): N10-formyl-THF N3, N9 (via amido group): Glutamine (Glutamine hydrolysis) C6: CO2 N1: aspartate

Question 49

PRPP synthetase (R5P --> PRPP) activators and inhibitors?

Answer 49

1. activators: PPi (pyrophosphate), Mg2+ (cofactor), 2,3-BPG 2. inhibitors: ADP, AMP, GDP, GMP (low energy)

Question 50

Inhibitors of Gln-PRPP-amidotransferase, adenylosuccinate synthase and IMP dehydrogenase? Activators of adenylosuccinate synthase and XMP-glutamine aminotransferase?

Answer 50

Question 51

**What AA's do all purine nitrogen atoms come from?

Answer 51

glutamine (N3, N9), aspartate (N1), and glycine (N7)

Question 52

How many steps in purine biosynthesis require formyl-tetrahydrofolate (THF)?

Answer 52

Two

Question 53

What is the branch point in purine biosynthesis where either GMP or AMP is then synthesized?

Answer 53

IMP (inosine 5'-monophosphate)

Question 54

**IMPT: What is the importance of regulating the pathways synthesizing IMP, ATP, and GTP? are

Answer 54

To control the total amounts of purines produced and the relative amounts of ATP and GTP