Uric A

Question 1

Humans: Urate is the end product of purine metabolism. Humans cannot convert urate to a more soluble form because they lack the enzyme ___.

Answer 1

uricase

Question 2

Hyperuricemia: Elevated levels of urate in humans can lead to gout and kidney damage because urate has poor solubility.

Question 3

What are the Sources of Purines:

Answer 3

From DNA and RNA: Purines such as adenine and guanine are key components of nucleic acids (DNA and RNA).

Dietary Sources: Purines come from the breakdown of ingested nucleic acids, particularly from meat rich in cells.

Endogenous Production: About two-thirds of urate is produced internally, while one-third comes from dietary purines.

Question 4

Nucleotides are essential building blocks for ______ Each nucleotide is made up of three components:

Answer 4

nucleic acids (DNA and RNA).

Nitrogenous Base: A molecule containing nitrogen with a structure that forms the “code” for genetic information.
Pentose Sugar: A five-carbon sugar. There are two types:
Ribose: Found in RNA.
Deoxyribose: Found in DNA (lacking one oxygen atom compared to ribose).
Phosphate Group: A molecule containing phosphorus and oxygen that links nucleotides together in a chain.

Question 5

Nucleoside =

Nucleotide =

Answer 5

Nucleoside = Nitrogenous base + Pentose sugar
Nucleotide = Nucleoside + Phosphate group

Question 6

What are the Types of Nitrogenous Bases? & their differences

Answer 6

There are two main categories of nitrogenous bases:

Purines: Larger, double-ring structures.

Adenine (A)

Guanine (G)

Pyrimidines: Smaller, single-ring structures.

(Examples include cytosine, thymine, and uracil)

Question 7

Give the Nucleotides and Nucleosides Examples

Answer 7

Nucleotides:

AMP (Adenosine Monophosphate): A nucleotide with adenine as the base.

ADP (Adenosine Diphosphate): A nucleotide with adenine and two phosphate groups.

ATP (Adenosine Triphosphate): A nucleotide with adenine and three phosphate groups.

Nucleosides:

Adenosine: Adenine + Ribose.

Guanosine: Guanine + Ribose.

Question 8

List examples of DNA and RNA Nucleotides

Answer 8

DNA Nucleotides (Purine):

dAMP (deoxyadenylate): Adenine + Deoxyribose + Phosphate group.

dGMP (deoxyguanylate): Guanine + Deoxyribose + Phosphate group.

RNA Nucleotides (Purine):

AMP (adenylate): Adenine + Ribose + Phosphate group.

GMP (guanylate): Guanine + Ribose + Phosphate group.

Question 9

Minor and Modified Bases
Besides the standard bases, there are also minor and modified forms that play specific roles in nucleic acid structure and function:
List examples

Answer 9

Xanthine
Hypoxanthine
7-Methylguanine
Dihydrouracil
5-Methylcytosine

Question 10

What are the Roles of Nucleotides

Answer 10

Nucleotides are vital for several cellular functions, including:

Building Blocks of DNA and RNA: Essential for storing and transferring genetic information.

Coenzymes: Assist enzymes in catalyzing reactions (e.g., NAD, NADP).

Signaling Molecules: Involved in cellular communication (e.g., cAMP, cGMP).

Energy Carriers: Provide energy for cellular processes (e.g., ATP).

Carriers of Metabolic Intermediates: Important in metabolism of carbohydrates, lipids, and proteins (e.g., CoA, FAD).

Question 11

Purines are synthesized by most tissues, with the ____ being the primary site.
Location: The pathway occurs in the _____ of cells.

Answer 11

liver
cytoplasm

Question 12

Explain the purine bio synthesis

Answer 12

Building the Purine Ring

Starting Material

Ribose-5-Phosphate: Think of this as the foundation or base on which the purine ring is built. This molecule comes from the Hexose Monophosphate (HMP) pathway, which is like a supply line providing the necessary starting material.

Initial Steps

Formation of PRPP (Phosphoribosyl Pyrophosphate):

Condensation of Pyrophosphate with Ribose-5-Phosphate: Imagine you’re starting to build a house (purine ring) on a plot of land (ribose-5-phosphate). The first thing you do is lay down a special brick (PRPP) to mark the beginning of construction.

Chemical Reaction: This involves attaching a pyrophosphate group (a kind of chemical component) to ribose-5-phosphate, forming PRPP. This is like placing the cornerstone of your house.

Incorporation of Glutamine:

Adding the Amino Group: Next, you add a specific part from glutamine (an amino group) to PRPP. This changes PRPP into phosphoribosylamine. Think of this step as adding the first structural beam to your house.

Release of Pyrophosphate: In this process, pyrophosphate is released, like removing a temporary support after placing the beam.

Catalyzing Enzyme: Amidophosphoribosyl transferase is the enzyme that makes this step happen. It’s like a worker who knows exactly how to place the beam correctly. This step is crucial because it sets the pace for the whole construction project.

Subsequent Steps

Addition of Glycine:

Forming Phosphoribosylglycinamide: Now, you add another building block (glycine) to phosphoribosylamine, forming phosphoribosylglycinamide. This is like adding more beams and walls to your house structure, making it more complete.

Formation of IMP (Inosine Monophosphate):

Series of Metabolic Steps: Through several more steps, involving different reactions and additions, the structure becomes a fully formed purine nucleotide.

First Fully Formed Purine Nucleotide: IMP is the first complete nucleotide formed, acting like the fully constructed frame of your house.

Conversion to AMP and GMP: IMP can then be modified further to form AMP and GMP, which are like adding finishing touches to the house to create different styles or rooms

Question 13

What are the Sources of Nitrogen for purine synthesis

All nitrogen atoms in the purine ring come from amino acids:e.g

Biosynthesis Utilizes:

Answer 13

Glutamine
Aspartate
Glycine

Utilizes:
Glycine (entire molecule)
Glutamine
ATP (energy source)
Folate (as N10-formyl-THF)
Aspartate
CO2

Question 14

What are the key regulators of purine synthesis?

Answer 14

Key Regulators

Committed Step: Amidophosphoribosyl transferase catalyzes the committed step in purine biosynthesis.

Activation: An increase in PRPP concentration activates amidophosphoribosyl transferase.

Inhibition: AMP or GMP individually inhibit amidophosphoribosyl transferase, and they can act synergistically for more potent inhibition.

Question 15

In Humans: The final product of breaking down purines (components of DNA and RNA) in humans is uric acid.
In Other Mammals: Many other mammals convert uric acid to a more water-soluble substance called ___ because they have an enzyme called uricase, which humans lack.

Answer 15

allantoin

Question 16

Nitrogen Excretion:
Although some nitrogen from purine breakdown is excreted as _______ most nitrogen in the body is excreted as ______ & why?

Answer 16

uric acid

urea, which is less toxic and more soluble in water.

Question 17

What are the Enzymes Involved purine breakdown?

Answer 17

Nucleotidases and Nucleosidases: These enzymes break down nucleotides (the building blocks of DNA and RNA) to release ribose (a sugar) and phosphate, leaving free bases (the purine molecules themselves).

Xanthine Oxidase: This enzyme converts xanthine, a breakdown product of purines, into uric acid. Think of it as the final step in the purine breakdown pathway.

Question 18

What’s the purpose of Purine Salvage Pathway

Answer 18

Purpose

Recycling: This pathway recovers and recycles purine bases from the breakdown of nucleotides to make new nucleotides. It’s like a recycling program for purine bases.

Efficiency: This process is important because it saves energy. Making new purines from scratch (de novo synthesis) is energy-intensive.

Significance in Certain Tissues

Tissues: It’s particularly important in tissues like red blood cells (RBCs), lymphocytes (a type of white blood cell), and to a lesser extent, the brain, where the de novo synthesis of purines is not very efficient.

Energy Conservation: Since making purines from scratch is costly in terms of energy, recycling them through the salvage pathway is economical.

Question 19

What are the Enzymes Involved purine salvage pathway

Answer 19

Hypoxanthine-Guanine Phosphoribosyl Transferase (HGPRT): This enzyme is crucial for attaching purine bases to phosphoribosyl pyrophosphate (PRPP) to form nucleotides again.

Adenine Phosphoribosyl Transferase (APRT): This enzyme also helps in recycling purine bases, though it’s less significant because the body produces less adenine.

Question 20

What does the salvage pathway do?

Answer 20

Recycling Process: The salvage pathway takes free purine bases (adenine, guanine, hypoxanthine) and combines them with PRPP to form their respective nucleotides (AMP, GMP, IMP).

Adenine+PRPP = AMP+PPi Guanine+PRPP = GMP+PPi Hypoxanthine+PRPP = IMP+PPi

Question 21

What are the exact dxs that might occur due to enzyme deficiency in the salvage pathway

Answer 21

Lesch-Nyhan Syndrome: This is a genetic disorder caused by the absence of HGPRT. Without this enzyme, the body can’t recycle purines efficiently, leading to an increase in purine synthesis and elevated levels of uric acid, which can cause severe gout and neurological symptoms.

Kelley-Seegmiller Syndrome: This is a less severe form of HGPRT deficiency, leading to less severe symptoms compared to Lesch-Nyhan syndrome.

Question 22

Purine Salvage Pathway
Definition:

Answer 22

A biochemical pathway for the recovery and recycling of purine bases from the degradation of nucleotides to resynthesize nucleotides.

Question 23

Importance: of Purine Salvage Pathway

Answer 23

Tissues: Essential in tissues like RBCs, lymphocytes, and to a lesser extent, the brain, where the de novo synthesis pathways are less active.

Energy Conservation: Economizes intracellular energy expenditure, given the high energy cost associated with de novo synthesis of nitrogen bases.

Question 24

Cliat the key enzymes of Purine Salvage Pathway/

Answer 24

Hypoxanthine-Guanine Phosphoribosyl Transferase (HGPRT)

Adenine Phosphoribosyl Transferase (APRT)

Note: APRT is less significant because adenine is generated in very small amounts.

Question 25

What’s the Salvage Pathways Function:

Answer 25

Adenine + PRPP → AMP + PPi

Guanine + PRPP → GMP + PPi

Hypoxanthine + PRPP → IMP + PPi

Hypoxanthine and guanine are collected and recombined with PRPP to form nucleotides through the HGPRT reaction.

Question 26

Clinical Syndromes: relating to Purine Salvage Pathway

Answer 26

Lesch-Nyhan Syndrome:

Caused by the absence of HGPRT.

Results in a 22-fold increase in purine synthesis and elevated uric acid levels in the blood.

Kelley-Seegmiller Syndrome:

Caused by partial deficiency of HGPRT.

Question 27

Production: About 2/3 of body urate is produced endogenously, and 1/3 comes from dietary purines.

Question 28

Excretion:____ of daily urate is excreted by the kidneys, and the rest by the intestines. In renal failure, intestinal excretion increases to compensate for decreased renal excretion.

Answer 28

75%

Question 29

Demographics: Males typically have higher plasma urate levels than females. Urate levels are higher in people of higher socio-economic status and in the obese

Question 30

Renal Handling of Urate: how?

Answer 30

Urate is freely filtered at the glomerulus.

Reabsorbed, secreted, and reabsorbed again in the proximal convoluted tubule (PCT) and distal convoluted tubule (DCT).

Question 31

Secretion Correlation: Urate secretion correlates with serum urate concentration; a small increase in plasma urate leads to a marked increase in urate excretion

Question 32

Hyperuricaemia: Most cases are due to defective elimination (underexcretion)

Question 33

What’s the primary and secondary cause of Increased Urate Formation which will cause Hyperuricaemia

Answer 33

Increased Urate Formation:

Primary:

Increased purine synthesis.

Idiopathic.

Inherited metabolic diseases.

Secondary:
Excessive dietary intake.
Disordered ATP metabolism (e.g., alcohol consumption).
Increased nucleic acid turnover (e.g., malignant diseases, psoriasis, cytotoxic drugs, rhabdomyolysis).

Question 34

What’s the primary and secondary cause of Decreased Renal Urate Excretion: which will cause Hyperuricaemia

Answer 34

Primary:

Idiopathic.

Secondary:
Chronic kidney disease.
Decreased Renal Secretion:
Low-dose salicylates.
Diabetic ketoacidosis (DKA).
Starvation ketosis.
Alcohol consumption

• Increased Renal Reabsorption:

Diuretics (thiazides).

Diabetes insipidus.

Question 35

What are the Inherited Causes of Hyperuricaemia

Answer 35

• Lesch-Nyhan Syndrome (L-NS):

X-linked recessive disorder.

Complete deficiency of hypoxanthine-guanine phosphoribosyl transferase (HGPRT).

• Kelley-Seegmiller Syndrome:

X-linked recessive disorder.

Partial deficiency of HGPRT, milder variant of L-NS.

• 5-Phosphoribosyl-1-Pyrophosphate Synthetase Overactivity:

Mainly X-linked recessive.
Increased production of 5-phosphoribosyl pyrophosphate

Question 36

What are the Metabolic Diseases (IEM) Causing Hyperuricemia?

Answer 36

Glycogen Storage Disease I

• Explanation: Glycogen Storage Disease type I leads to hyperuricemia due to impaired glucose-6-phosphatase activity, causing overproduction and underexcretion of uric acid.

Hereditary Fructose Intolerance (HFI)

• Explanation: HFI results in hyperuricemia primarily because of deficient fructose-1-phosphate aldolase, leading to uric acid overproduction

Glycogen Storage Disease types III & IV
- Explanation: These types also contribute to hyperuricemia, albeit less prominently than GSD I and HFI, due to abnormal glycogen metabolism affecting uric acid levels.

Question 37

What are the conditions cause hyperuricemia through a combination of increased uric acid production and impaired excretion mechanisms.

Answer 37

Alcohol, GSD I, and HFI

Question 38

Causes of Hypouricemia

Answer 38

• Decreased Urate Production
  Xanthine Oxidase Deficiency

Hereditary Xanthinuria: Autosomal recessive condition resulting in low uric acid production due to xanthine oxidase deficiency.

Liver Disease: Loss of xanthine oxidase activity in liver pathologies contributes to reduced uric acid synthesis.

Allopurinol: Inhibitor of xanthine oxidase, prescribed to lower uric acid levels in conditions like gout.

Purine Nucleoside Phosphorylase (PNP) Deficiency: Impaired enzyme activity leads to decreased uric acid production.

xanthine oxidase

Question 39

Hypouricemia is caused by Increased Urinary Excretion in which dxs condition?

Answer 39

Familial Renal Hypouricemia: Autosomal inherited disorder causing excessive uric acid excretion by the kidneys.

Fanconi’s Syndrome: A renal tubular disorder resulting in increased urinary excretion of uric acid.

Plasma Volume Expansion: Conditions like intravenous fluid overload increase uric acid excretion.

Drugs: High-dose salicylates, cotrimoxazole, losartan, and vegetarian diets can enhance uric acid excretion.

Question 40

Tests for hypo/ hyper uricemia?

Answer 40

Biochemical Evaluation

Elevated Serum Uric Acid: Levels above 8 mg/dL diagnose hyperuricemia, associated with conditions like gout and nephrolithiasis.

Urinalysis: Detects microscopic hematuria, uric acid crystals, and
Low urinary pH (<5.5), indicative of uric acid nephrolithiasis.

24-Hour Urine Uric Acid Collection: Levels above 800 mg/day suggest hyperuricosuria, aiding in determining uric acid production or excretion abnormalities.

Other Laboratory Studies: Including CBC, CMP, lipid profile, HgA1c, calcium, and phosphate, useful for identifying underlying diseases affecting uric acid metabolism.

Question 41

Treatments for urecemia

Answer 41

Dietary Restriction: Low-purine diets to reduce uric acid production.

Asymptomatic Hyperuricemia: Treatment remains controversial.

Promote Uric Acid Excretion: Alkalinization of urine to enhance uric acid solubility and excretion.

Xanthine Oxidase Inhibitors: Drugs like allopurinol inhibit uric acid production by blocking xanthine oxidase.

Treat Underlying Causes: Address metabolic disorders contributing to abnormal uric acid metabolism.

Monitoring: Both clinical and laboratory assessments are crucial to assess treatment efficacy