Transcript Purines and Pyrimidines

Nucleic Acids
(DNA, RNA)
By: Micheal, Robert, & Narjes
Nucleic Acids (NA) are nonessential nutrients, because they can be synthesized in the
body.
Nucleic Acid: polymeric macromolecules made from nucleotide monomers
Nucleotide are Building block of nucleic acid, The two DNA strands are made of two
monomer units called nucleotides. Consists of purine/pyrimidine base ,
ribose/deoxyribose and phosphates.
Nucleoside: Consist of purine or pyrimidine base, and ribose or deoxyribose
Purines and Pyrimidines are nitrogenous bases that make up the two different kinds of
nucleotide bases in DNA and RNA.
• adenine and guanine are purines
• thymine, uracil and cytosine are pyrimidines
Purine: A nitrogen-containing substance derived from uric acid
Purine bases: Adenine and Guanine
Pyrimidine: A nitrogenous base with a six-sided structure
Pyrimidine bases: Cytosine, Thymine, Uracil
Base Paring in DNA: A=T, C=G
Base Pairing in RNA: A=U, C=G
Main functions:
1. DNA/RNA Replication
Short Term energy storage of ATP
Mouth: Responsible for mechanical digestion Mastication and deglutition
Esophagus: Responsible for transportation of the
bolus to the stomach - Deglutition and Peristalsis.
Stomach: Responsible for denaturation of Nucleic
Acids and beginning chemical digestion
Small Intestine: Responsible for completing chemical
digestion by way of enzyme release via pancreatic
juice
Digestion in the Stomach
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It has been found that human gastric juice is able to
significantly digest ingested NAs. Further study
demonstrates that the dominant enzyme in gastric juice,
pepsin, was responsible for this activity.
The harsh pH of the stomach is responsible for
denaturing the DNA strands into individual strands.
From there, Pepsin digests NAs at specific sequences,
leaving them in fragments with a 3′-phosphate end and a
5′-OH end.
The active site for cleaving phosphodiester bonds is
believed to be the same as that used for digesting
peptide bonds in proteins.
Some research would argue then that chemical digestion
starts in the stomach rather than the small intestine as
others would suggest.
Digestion in Small Intestine
- Nucleic acid fragments then enter the small intestine from the stomach dissolved in
gastric chyme
- As gastric chyme enters the duodenum, the pancreas delivers two enzymatic
nucleases:
1. Ribonuclease (RNAse)
2. Deoxyribonuclease (DNAse)
There are two types of nucleic enzymes:
Enzymes that break
Enzymes that break & Exonucleases
Endonucleases
apart a
polynucleotide chain
by cleaving the
phosphodiester
bonds between
nucleotides within a
polynucleotide chain.
apart a polynucleotide
chain by cleaving
successive nucleotides
from the ends of the
polynucleotide
molecule.
1. Ribonuclease: catalyzes the breakdown of RNA into ribonucleotides.
2. Deoxyribonuclease: catalyzes the breakdown of DNA into deoxyribonucleotides.
These individual ribo- and deoxyribonucleotides are still too large and are required to be
broken down into smaller components until they can be absorbed in the small intestine.
Brush Border Enzymes
Further digestion occurs at the microvilli in
the S.I. from two enzymes:
1. Phosphatases - catalyze the cleavage of a
phosphate group from a nucleotide to
form a nucleoside and a phosphate ion.
2. Nucleosidases - catalyze the breaking of
the covalent bond between the
nitrogenous base and the pentose sugar
of a nucleoside.
These Enzymes are responsible for breaking
nucleotides into their individual absorbable
components: phosphate ions, nitrogenous
bases & pentose sugars
Nucleic acid absorption
Nucleic acid Absorption end products: mainly occur in the duodenum and jejunum of
the small intestine, at the intestinal villus.
All nucleic acid are absorbed as:
❏ Nitrogenous bases
❏ Pentose sugar
❏ Phosphate ions
Membrane transport proteins carry the products of nucleotide digestion into epithelial
cells from the lumen. Some involve active transport, other involved secondary active
transport(direction of its concentration gradient).Through diffusion , the products of
nucleotide digestion are transported from the intestinal epithelial cells:
❏ Across the basolateral membrane
❏ Into the interstitial fluid
❏ And finally into the blood capillaries
of the intestinal villi
The nucleotide digestion products
are transported by blood circulation
to the liver and other tissues where
they undergo further degradation.
Uric acid which is the end product of
purine degradation exist as sodium
ureate in plasma. Maximum amount
of sodium ureate that can dissolve in
the blood plasma is about 7 mg/100
ml. At this point there will be
saturation of blood with sodium
ureate.
Purine Catabolism
Nucleotides are absorbed into intestinal mucosa cells, where they are degraded to three
components: Base, Pentose, and phosphate.
Pentose is absorbed but base is degraded and excreted. Duodenum and Jejunum absorb
the products in the epithelial cells.
The end product of purine catabolism is uric acid in humans.
Hyperuricemia
•An abnormally high level of uric acid in the blood.
•High levels of uric acid in the blood can lead to gout, which is a medical condition characterized by
recurrent attacks of acute inflammatory arthritis.
Gout
Absorption
Occurs in duodenum and jejunum of small intestines
Absorbed at the intestinal villus.
Goes from lumen to epithelial cells then across the basolateral membrane into the
interstitial fluid into the blood and then to the liver and other tissues for further
degradation.
1- De Novo Synthesis
The Main synthesis pathway of nucleotides.
De Novo synthesis creates purine nucleotides through anabolism.
Can be Divided into two phases
Stage one of De Novo Synthesis
formation of inosine monophosphate
Requires five moles of ATP, two moles of glutamine, one mole of glycine, one mole of CO2,
one mole of aspartate and two moles of formate.
PRPP Synthetase
R5P+ATP--------------------->PRPP+AMP
amidophosphoribosyltransferase
H2O+PRPP+Glutamine---------------------->PRA+ Glutamate+ PPi
Glutaminase domain: Glutamine --> NH3+Glutamate
Phosphoribosyltransferase domain: PRPP+ NH3 → PRA+PPi
10 step reaction for IMP
PRPP+H20+glutamine------->Glutamate+Pi
2. Glycine+ATP+PRA------------------------->Glycinamide ribotide+ADP+Pi
3. GAR+N10-formyl-THF-------------------->THF +Formylglycinamide ribotide
4. FGAR+ATP+Glutamine----> Formylglycinamine ribotide+ADP+Pi+Glutamate
5. FGAM+ATP------------------------>ADP+Pi+5 aminoimidazole ribotide
6. AIR+CO2-------------------------> Carboxylaminoimidazole ribotide
7. Aspartate+ATP---->ADP+Pi+5-aminoimidazole-4 (N-Succinylocarboxamide)
ribotide
8.SAICAR--------->Fumerate+5-aminoimidazole-4-carboxylamide ribotide
9.AICAR+ N10 formyl-THF-------------> THF+ FAIRCAR
10. FAICAR+H20 IMP
Stage two: conversion of IMP to either AMP or GMP
Route one IMP to GMP
Adenylosuccinate synthetase(ADSS)
Aspartate+GTP+IMP----------------------> GDP+Pi+ Adenylosuccinate
Adenylosuccinate lyase (ADSL)
Adenylosuccinate----------------------> Fumerate+ AMP
Route Two IMP to GMP
IMP dehydrogenase 1
IMP+H20+NAD+--------------->NADH+H+Xanthylate
GMP Synthetase
Xanthylate+ Glutamine+ATP---------------> AMP+PPi+ Glutamate +GMP
De Novo Pathway
PRPP
IMP
GMP
UMP
UDP
AMP
DUDP
DUMP
DTMP
CTP
De Novo Pathway Summary
Purine ring is built from one or a few atoms at a time and attached to the
ribose ring throughout the process.
Pyrimidine ring is synthesized from orotate and attached to the ribose
phosphate.
Ribose phosphate is converted to common pyrimidine nucleotides
The enzymes involved in De-novo synthesis are present as large multienzyme
complexes.
Salvage pathway
Used to recover the Nucleosides and bases that formed from the degradation of DNA
and RNA
Purine salvage pathway
RNA or DNA
GMP
Purines
AMP
GMP
HGPRT
(Hypoxanthine-guanine
phosphoribosyltransferase)
IMP
Adenosine
Adenosine
Deaminase
Hypoxanthine
Hypoxanthine
& Guanine
Inosine
AMP
GMP
IMP
AMP
Guanosine
adenosine
Product pathways
Guanine
inosine
hypoxanthine
xanthine
uric acid
Defecation Reflex
- After electrolytes and H2O have been
absorbed, the waste passes to the
rectum from the sigmoid colon.
- This causes an increase in rectal
pressure, and stretch receptors send a
signal to the spinal cord causing the
urge to defecate.
- leads to contraction of sigmoid colon,
and rectum and relaxation of internal
anal sphincter muscles.
- Voluntary muscle response occurs due
to habit either allowing or disallowing
defecation. If it is convenient to do so
external sphincter muscles relax.
Defecation Reflex
•During defecation the longitudinal rectal muscles contract to increase pressure.
•Defecation is normally assisted by taking a deep breath and trying to expel this air
against a closed glottis causing contraction of abdominal and pelvic skeletal muscles.
- This forced defecation is a similar sensation to lifting a heavy object or
performing the valsalva maneuver.
Valsalva Maneuver
•Forcefully expulsing air while plugging your
nose and closing your mouth
•Clears pressure in the middle ear (air travel,
scuba diving, pressurization of a space suit)
•The Valsalva Maneuver aids in creating
pressure in the chest such that the thorax
exerts pressure on the digestive tract in the
abdomen
•Used clinically in a variety of ways: diagnosis
of cardiovascular, neurological or urogenital
issues, palpating subclavicular lymph nodes,
etc.
4 stages:
Valsalva Maneuver and the heart
1. Initial Pressure Rise - pressure rises in the
chest forcing blood out of pulmonary
circulaiton = slight increase in stroke volume
2. Reduced Venous Return and Compensation return of blood to the heart is impeded by
pressure in the chest = CO and SV falls
3. Pressure Release - pressure on chest is
released allowing pulmonary vessels and aorta
to return to reexpand = venous blood can
enter the heart and chest
4. Return of Cardiac Output - rapid increase in
CO peaking above baseline and returning to
normal after a brief stint at elevated levels
Valsalva Maneuver Cont.
- Any deviation from this normal pattern would suggest abnormal heart
function or perhaps improper autonomic nervous control of the heart.
- The valsalva maneuver can be used to diagnose issues with cervical
nerves. The pressure build up can often times cause radiating pain and
help to identify a nerve impingement
- subclavicular lymph node enlargement is usually an indicator of cancers.
Having a patient perform a valsalva maneuver pushes the lungs up making
lymph nodes more accessible for palpation.
- Forcing yourself to urinate of defecate is a similar pressure felt to valsalva
maneuver, and urogenital leakage during such demonstration could be
indicative of sphincter deficiency.
Works Cited
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500949/figure/f6/
https://www.ncbi.nlm.nih.gov/pubmed/26168909
http://www.johnwiley.net.au/highered/interactions/media/Energy/content/Energy/dig6a/bot.htm
http://science-forums.com/index.php?action=gallery;sa=slideshow;id=776
Fox, Stuart I., Human Physiology 13th ed., New York, NY: McGraw-Hill 2013 Pgs. 619-659
Checklist:
Group 4 Requirements: Digestion of Nucleic Acids (DNA and RNA):
Chemical Structures; Function/Digestion in Mouth?; Esophagus?;
Stomach?; Small Intestine?;
Absorption: where? how? all enzymes? fate?
Topics to mention and terms to define for the class: pyrimidine; purine;
base; endonuclease; nucleotide; nucleoside; exonuclease;
nucleotidases; de-novo synthesis; salvage pathway; purine degradation
into uric acid (gout) and hyperuricemia.
Defecation Reflex;
Valsalva’s maneuver;