Scribd
Upload
33 views27 pages

Salvage Pathway

The document discusses the salvage pathway of purine synthesis, highlighting the roles of enzymes like APRT and HGPRT, and their significance in preventing waste and supporting tissue function. It also covers inhibitors of purine synthesis used in cancer treatment, the degradation of purines leading to conditions like gout, and specific syndromes such as Lesch-Nyhan syndrome caused by enzyme deficiencies. Treatment strategies for gout, including reducing uric acid production and inflammation, are also outlined.

Uploaded by

Lenda Limboo
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
33 views27 pages

Salvage Pathway

The document discusses the salvage pathway of purine synthesis, highlighting the roles of enzymes like APRT and HGPRT, and their significance in preventing waste and supporting tissue function. It also covers inhibitors of purine synthesis used in cancer treatment, the degradation of purines leading to conditions like gout, and specific syndromes such as Lesch-Nyhan syndrome caused by enzyme deficiencies. Treatment strategies for gout, including reducing uric acid production and inflammation, are also outlined.

Uploaded by

Lenda Limboo
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
You are on page 1/ 27

SALVAGE PATHWAY

PURINE SYNTHESIS
• Adenine phosphoribosyl transferase (APRT)
Adenine + PRPP AMP + Ppi

• Hypoxanthine-Guanine phosphoribosyl transferase (HGPRT)


Guanine + PRPP GMP + Ppi
Significance : a. Simpler and more cost effective
b. Prevents wastage of raw materials
c. Important for tissues like brain and erythrocytes(enzyme deficient –
PRPP amido transferase )
Regulation
INHIBITORS OF PURINE SYNTHESIS

• Nucleotide biosynthesis pathways are good targets for


anticancer/antibacterial strategies. Widely used to control
cancer(Chemotherapeutic Agent).
= By interfering, inhibiting or blocking biosynthesis pathway of Purine
nucleotides and further block synthesis of DNA, RNA, and proteins.
1. Analogues of PABA
Sulphonamides N10Formyltetr
ahydrofolate

N10Formyltetr
ahydrofolate
• Folic acid is required for THF synthesis .
• Decreased folic acid >> decreased THF synthesis >> decreases Purine
synthesis
• Diminished synthesis of purine nucleotides in bacterial cells results ,
>>diminished bacterial cell growth and proliferation
• Sulfonamides structural analogs of PABA inhibits Folate Synthesis
in microbes.
• It indirectly inhibit Purine biosynthesis
• Since THFA is a carrier of one carbon moiety
2. ANTIFOLATES

• Methotrexate and Aminopterin Folate analogs are inhibitors of


Folate Reductase which form THFA.
• Presence of these inhibitors affect the reduction of Folate to THFA.
• THFA is not available for 1 Carbon moiety transfer in Purine
biosynthesis.
• De novo Purine biosynthesis depends on folic acid
compounds at steps 4 and 10
• For this reason, antagonists of folic acid metabolism
indirectly inhibit Purine formation and, in turn, nucleic
acid synthesis, cell growth, and cell development
• Rapidly growing cells, such as infective bacteria and fast-
growing tumors, are more susceptible to such agents
Hence ,
Folate Analogs as Antimicrobial and Anticancer Agents
3. Amino Acid (Glutamine) Antagonists
Azaserine (AS) is an analog of Glutamine.
It inhibits the steps of Purine (as well as Pyrimydine) in which
Glutamine donates the Nitrogen group (N3 & N9) AND
IMP  GMP
UTP  CTP
4. 6-Mercaptopurine inhibits conversion of IMP to AMP

5. 5’-Flurouracil is a structural analogues of bases of Nucleoside.


Incorporates into DNA or RNA but becomes functionally inactive
.......Arrests cell division ....hence used in the treatment of cancer
Degradation of Purine
Nucleotides
Clinical Correlates

• Uric acid is a NPN, waste excreted end product of Purine catabolism.


• The normal concentration of uric acid in the serum of adults is in the
range of 3-7 mg/dl.
• The rate of uric acid excretion by the normal adult human is about 0.6
g/24 h in urine, arising in part from ingested purines and in part from
the turnover of the purine nucleotides of nucleic acids.
GOUT
• Gout derived from Latin Word:
GUTTA
• Meaning ‘A drop of liquid’
• Gout is a common metabolic
disorder of Purine metabolism
characterized by :
• Persistent Hyperuricemia
• Hyperuricaciduria and
• Joint pain
• Gout, is a disease of the joints, usually in males, caused by an
elevated concentration of uric acid in the blood and tissues.
• The joints become inflamed, painful, and arthritic, owing to the
abnormal deposition of crystals of sodium urate.
• The kidneys are also affected, because excess uric acid is deposited in
the kidney tubules.
Gout:“Disease of Kings”

• Rich foods have a higher


concentration of Nucleoproteins.
• ORGAN MEATS
• This could cause major problems • SEAFOOD
for a person afflicted with Gout. • LENTILS
• PEAS
• ASPARAGUS
• YEAST
• BEER
Types and Causes Of Gout

• Primary Gout (Genetic Cause)


• Secondary Gout

Basic Cause Of Gout


• Hyperuricemia

• Over Production Of Uric acid


• Under Excretion Of Uric acid
Primary Gout
• Primary Gout is an inherited sex linked recessive disorder.
• Affecting more Males.
• What is the Basic cause of primary Gout
genetic cause.
• It has Enzyme defects concerned with:
• Over Production Of Purine Nucleotides than the
functional use.
• Over catabolism of Purine Nucleotides
• Results in Hyperuricemia
Enzyme Defects
Causing Primary Gout

1. PRPP Synthetase
(Increased Activity))
2. PRPP Glutamyl Amido Transferase
(Increased Activity)
3. HGPRTase : Deficiency of enzyme
- Decreased Activity)
4. Glucose 6 Phosphatase :
Deficiency of enzyme
- Decreased Activity
Secondary Gout
It is an acquired cause:
• Increased production in Uric acid (10%)
• Reduced Excretion Rate (90%)
Conditions Of Secondary Gout
Increased production in Uric acid : (10%)
In some pathological states where there is abnormal and excessive
breakdown of cells releases Nucleic acids and Nucleotides. Whose
catabolism produces increased Uric acid levels (Hyperuricemia)
• Rapidly growing malignant tissues e.g Leukemia, Lymphomas,
Polycythemia
• Increased tissue breakdown after Treatment Of Large Tumors
• Increased tissue damage due to Traumatic Conditions
• Radiation Injury
Reduced Excretion Rate
• Renal failure
• Treatment with thiazide diuretics which inhibits tubular secretion of
uric acid
• Lactic acidosis and ketoacidosis due to interference with tubular
secretion
Clinical Manifestations Of Gouty Arthritis
Gouty Arthritis
Main Symptoms
• Joint Pain
• Affects one or more joints : hip, knee, ankle, foot, shoulder,
elbow,wrist, hand, or other joints
• Great toe/big toe joint (Metatarsophalangeal) most common first
manifestation (Monoarticular)
• , ankle and knee are most common
• Swelling of Joint
• Stiffness
• Warm and red
• Possible fever
• Tophi/Skin Lump
• which may drain chalky material
Treatment of Gout
Targets
• Decreasing Uric acid production
Allopurinol (Hypoxanthine analogue)  Alloxanthine
Xanthine Oxidase
• Increasing its excretion : By Uricosuric drugs (e.g Salicylates ,
Probenecid) >> decreases renal reabsorption of Uric acid from
renal tubules

• Reducing Inflammation : By using anti-inflammatory drug


(Colchicine, NSAIDS : Diclofenac, Ibufren )to arrest pain and
inflammation in Gouty arthritis
Lesch Nyhan Syndrome

• Enzyme deficient : HGPRT


• Named after the investigators Michael Lesch and William L. Nyhan
who first described in the year 1948 .
• Males are affected (X- linked )
Characteristic feature of the syndrome

• Mental retardation is the predominant abnormality


Low capacity for denovo biosynthesis ; therefore a complete deficiency
of the salvage enzymes damages the brain by depriving it of purine
nucleotides
Delayed motor development
Unique feature : Self mutilating behaviour
• Hyperuricemia (high concentration of uric acid in the blood) causing
uric acid nephropathy followed by death at an early age
Lesch-Nyhan Syndrome

You might also like

pFad - Phonifier reborn

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.


Alternative Proxies:

Alternative Proxy

pFad Proxy

pFad v3 Proxy

pFad v4 Proxy