B1W2 Mtc Nucleotide Metabolism: Purines

Front 1

General synthesis of Purines

Back 1

Hypoxanthine turns into adenine with 6' amination

Hypoxanthine is oxidized into xanthine and then via amination into guanine

Front 2

General synthesis of pyrimidines

Back 2

uracil to cytosine via amination OR thymine via methylation

Front 3

Nomeclature example with uracil

Back 3

Uracil (U) would be uridine with an added sugar

With an added phosphate, it would be uridylic acid or UMP

dUTP would be when it has three phosphates and deoxyribose over ribose

Front 4

Outline of De Novo Pathway

Back 4

PRPP --> phosphoribosylamine --> IMP (completed ring)

From IMP: S-AMP to AMP

OR IMP to XMP to GMP

Linear synthesis pathway: PRPP to IMP

Branch point pathway: IMP to AMP/GMP

Front 5

What to know of linear synthesis pathway

Back 5

--base built onto sugar and phosphates; loses them

--5 ATP

--glutamine, glycine, aspartate gave us nitrogens

--formate and CO2 provide carbons (as well as glycine, 2 carbons)

--since amino acids are used to make nucleotide, this must be related to amino acid synthesis

Front 6

Branch point synthesis pathway: IMP to AMP

Back 6

1. Aspartate and GTP have an amine replace 2' oxygen on ring (adenylosuccinate)

2. Fummartate eliminates bulky group so top of ring has only NH2 (AMP)

Front 7

Branch point synthesis pathway: IMP to GMP

Back 7

1. NAD+ and H2O adds oxygen to 6' carbon through oxidation (XMP)

2. Glutamine and ATP add NH2 to 6' carbon, creating GMP

Front 8

PRPP Synthetase

Back 8

Makes PRPP from D-ribose-5-phosphate using ATP

Used elsewhere in body, so this is a non-commited step

Front 9

ATase

Back 9

Gets rid of phosphates in first committed step of pathway, so is RATE LIMITING and controlled allosterically by end products

--when purine nucleotides are up, forms dimer that inhibits active sites

--when PRPP up, dimer falls apart and active sites exposed

Front 10

Getting purines from MP to DP

Back 10

Need ATP and base specific kinases

--adenylate kinase (maintains 100ATP for every 1-ADP and 1 AMP)

--guanylate kinase

Front 11

Getting purines from DP to TP

Back 11

Not base specific, just need enzyme nucleoside diphosphate kinase

This is also used for pyrimidines

Front 12

Regulation of Purine De Novo Synthesis

Back 12

--AMP/GMP inhibit PRPP synthetase and ATase

--AMP inhibits adenylosuccinate synthetase but activates GMP synthase

--GMP inhibits IMP dehydrogenase but activates adenylosuccinate synthetase

--PRPP activates ATase

Front 13

AMP catabolic pathway (breaking down)

Back 13

First two steps can be switched

1. Deamination removes C-6 amino group with AMP deaminase, creating IMP

2. Dephosphorylation with substrate specificity (5' nucleotide) removes phosphate from pentose sugar, creating inosine

3. Purine nucleoside phosphorylase removes sugar, creating hypoxanthine

4. xanthine oxidase creates xanthine

5. xanthine oxidase or dehydrogenase creates uric acid

Front 14

Why can we switch the first two steps in the AMP catabolic pathway?

Back 14

Adenosine helps vasodilation in ischemia

IMP helps make ATP after exercise

Body will make one or the other depending on state

Front 15

GMP Catabolic pathway

Back 15

1. 5' nucleotidase dephosphorylates from sugar, creating guanosine

2. Purine nucleoside phosphorylase removes sugar, creating guanine

3. Gunase removesC-2 amino group, creating xanthine

4. Xanthine oxidase or dehydrogenase ceates uric acid

Front 16

Xanthine dehydrogenase/oxidase to uric acid

Back 16

Both do same thing (break down purines to uric acid) and from same mRNA

XO is a modification in low O2 env. like ischemia/stroke

XDH uses NAD as e- acceptor, i.e. in cell resp.

XO uses O2 as e- acceptor if cell resp. not occuring, making hydrogen peroxide which leads to free radicals

Front 17

Problem with too much uric acid

Back 17

Hyperuricemia or GOUT!

Uric acid crystalizes and damages tissues

Front 18

Primary inherited gout

Back 18

overexpression of PRPP synthetase

OR

defect in urate renal transport proteins

OR

HPRT needed for salvage pathway inhibited

Front 19

Secondary gout

Back 19

due to drugs or eating too much meat

Front 20

To treat gout

Back 20

Use alloxanthine

Inhibits ATase and XDH because it LOOKS like a base and tells our body not to make or break down any more nucleotides

Front 21

Xanthinuria

Back 21

Deficiency of xanthine dehydrogenase, make too much xanthine and, like uric acid, it builds up

No cure for it, just must control diet

Front 22

Immunodeficiency Diseases w/ Catabolic Pathway of Purines

Back 22

Deficiency of adenosine deaminase=SCIP, bubble boy disease w/ T and B cells messed up

Deficiency of PNP=impaired T cell fn.

Both are steps needed to rid sugar of guanosine, adenoside or IMP; instead, since inhibited, it leads to more dATP or dGTP, which tells ribonucleotide reductase to stop

This causes a stop in DNA synthesis, so poor T-Cell and B-Cell development occurs

Front 23

Purine Nucleotide Salvage pathway

Back 23

Normal metabolic pathway, tries to avoid making them bc it's a 5 ATP loss every time

Front 24

Recycling purine bases (salvage pathway)

Back 24

Need Adenine, PRPP and adeninephosphoribosyltransferase (APRT)

If guanine/hypoxanthine, need that, PRPP and HPRT

Example: Adenine + PRPP --> AMP + PPi

Front 25

Recycling purine nucleosides

Back 25

Need ATP and either adenosine/guanosine

Front 26

Deficiency of HPRT=Lesch-Nyhan Syndrome

Back 26

HPRT lacking, X linked disease

Can't recycle nucleotides, so PRPP and ATase not inhibited and keep making more and more nucleotides

Allopurinol fixes gout, but not the neurological issues

High HPRT is needed in the brain, so without it development is stalled