Nucleotide : Metabolism Pathway
Nucleotide Metabolism: Introduction & De Novo Purine Synthesis
To begin our journey, it is essential to clearly define and distinguish between nucleotides and nucleosides, understand their basic chemical structure, and appreciate their diverse and vital roles in biological systems.
I. Introduction to Nucleotides and Nucleosides
A. Definition and Components
1. Nucleoside
A molecule composed of two main parts:
- A Pentose Sugar: A 5-carbon sugar (either ribose or deoxyribose).
- A Nitrogenous Base: A heterocyclic ring structure containing nitrogen.
The Bond: The nitrogenous base is attached to the C1' carbon of the pentose sugar via a β-N-glycosidic bond.
2. Nucleotide
A Nucleotide is simply a Nucleoside with one or more Phosphate groups attached.
- Attachment: The phosphate group(s) are typically attached to the C5' carbon of the pentose sugar via an ester bond.
- Note: They can also be attached to the C3' carbon (less common, but important in RNA processing).
- • Monophosphate (NMP): One phosphate (e.g., AMP).
- • Diphosphate (NDP): Two phosphates (e.g., ADP).
- • Triphosphate (NTP): Three phosphates (e.g., ATP).
B. Pentose Sugars
The type of pentose sugar determines whether the nucleotide is for RNA or DNA.
- Found in Ribonucleosides and Ribonucleotides (RNA).
- Structure: It has a Hydroxyl (-OH) group at the C2' position.
- Found in Deoxyribonucleosides and Deoxyribonucleotides (DNA).
- Structure: It has a Hydrogen (-H) atom at the C2' position.
- Meaning: "Deoxy" literally means "lacking oxygen."
C. Nitrogenous Bases
These are cyclic, planar, relatively water-insoluble compounds that absorb UV light. They are categorized into two classes based on ring structure.
1. Purines (Double Ring)
Characterized by a double-ring structure (a six-membered pyrimidine ring fused to a five-membered imidazole ring).
The two major purine bases are:
- Adenine (A): Often designated with a single amino group.
- Guanine (G): Contains both an amino and a carbonyl group.
2. Pyrimidines (Single Ring)
Characterized by a single-ring structure (a six-membered heterocyclic ring).
The three major pyrimidine bases are:
- Cytosine (C): Contains an amino group.
- Thymine (T): Found only in DNA. Contains a methyl group at the C5 position.
- Uracil (U): Found only in RNA. Lacks the methyl group present in thymine.
D. Naming Conventions (Nomenclature)
| Base | Nucleoside (Ribose) | Nucleotide (Ribose-MP) | Nucleoside (Deoxyribose) | Nucleotide (Deoxyribose-MP) |
|---|---|---|---|---|
| Adenine (A) | Adenosine | Adenylate (AMP) | Deoxyadenosine | Deoxyadenylate (dAMP) |
| Guanine (G) | Guanosine | Guanylate (GMP) | Deoxyguanosine | Deoxyguanylate (dGMP) |
| Cytosine (C) | Cytidine | Cytidylate (CMP) | Deoxycytidine | Deoxycytidylate (dCMP) |
| Uracil (U) | Uridine | Uridylate (UMP) | - (rarely found in DNA) | - |
| Thymine (T) | Ribothymidine (rare) | Ribothymidylate (rTMP) | Deoxythymidine | Deoxythymidylate (dTMP) |
Note: For deoxyribonucleotides, the 'd' prefix is used (e.g., dATP, dGMP).
Note: Thymine is predominantly found in DNA. While "ribothymidine" exists, uracil is the primary pyrimidine in RNA.
E. Major Physiological Functions of Nucleotides
Nucleotides are far more than just building blocks for nucleic acids; they play incredibly diverse and crucial roles in almost every aspect of cellular life.
1. Building Blocks of Nucleic Acids
- DNA (Deoxyribonucleic Acid): Genetic material, stores and transmits hereditary information. dNTPs (dATP, dGTP, dCTP, dTTP) are polymerized to form DNA.
- RNA (Ribonucleic Acid): Involved in gene expression (mRNA, tRNA, rRNA), regulation, and catalysis. NTPs (ATP, GTP, CTP, UTP) are polymerized to form RNA.
2. Energy Currency of the Cell
- ATP (Adenosine Triphosphate): The primary energy-carrying molecule. Hydrolysis of its high-energy phosphate bonds releases energy to drive various cellular processes (muscle contraction, active transport, biosynthesis).
- GTP (Guanosine Triphosphate): Also an important energy source, particularly in protein synthesis (translation) and signal transduction.
3. Components of Coenzymes
Many essential coenzymes, critical for enzymatic reactions, are derivatives of nucleotides:
- NAD+ (Nicotinamide Adenine Dinucleotide): Derived from ATP. Involved in redox reactions (electron carrier).
- FAD (Flavin Adenine Dinucleotide): Derived from ATP. Involved in redox reactions.
- Coenzyme A (CoA): Derived from ATP. Involved in acyl group transfer reactions (e.g., fatty acid metabolism, TCA cycle).
4. Regulatory Molecules and Signal Transduction
- cAMP (cyclic Adenosine Monophosphate): A ubiquitous second messenger in signal transduction pathways, mediating the effects of many hormones (e.g., adrenaline).
- cGMP (cyclic Guanosine Monophosphate): Another important second messenger, involved in processes like vasodilation and vision.
- ADP, AMP: Allosteric regulators of many enzymes (e.g., in glycolysis, gluconeogenesis).
5. Activated Intermediates in Biosynthesis
- UDP-Glucose: Involved in glycogen synthesis.
- CDP-Diacylglycerol: Involved in lipid synthesis.
- S-Adenosylmethionine (SAM): A methyl group donor in numerous methylation reactions (not strictly a nucleotide but derived from ATP and methionine).
II. De Novo Synthesis of Purine Nucleotides
"De novo" means "from scratch," and indeed, the purine ring is constructed from small, simpler precursors in this pathway. This process primarily occurs in the liver, but also in other rapidly dividing cells.
A. Overall Pathway: Building the Purine Ring on PRPP
Unlike pyrimidine synthesis where the base is formed first and then attached to the sugar, purine synthesis begins with the sugar and builds the ring directly upon it.
α-D-Ribose-5-Phosphate (a product of the Pentose Phosphate Pathway).
- Ribose-5-phosphate is converted to 5-Phosphoribosyl-1-Pyrophosphate (PRPP).
- Enzyme: PRPP Synthetase (Ribose Phosphate Pyrophosphokinase).
- Energy Cost: ATP is consumed, and pyrophosphate (PPi) is released.
- Significance: PRPP is an activated pentose sugar that is a key precursor not only for purine synthesis but also for pyrimidine synthesis, NAD+ synthesis, and salvage pathways.
- The pyrophosphate group of PRPP is replaced by an amino group, forming 5-Phosphoribosyl-1-amine.
- Enzyme: Glutamine:PRPP Amidotransferase (this is the rate-limiting and committed step of purine synthesis).
- Nitrogen Source: The amino group comes from the amide nitrogen of Glutamine.
- Regulation: This enzyme is highly regulated (feedback inhibited by AMP, GMP, and IMP).
The purine ring (specifically the imidazole ring, followed by the pyrimidine ring) is built in a series of ten steps, consuming energy (ATP) and incorporating atoms from various small molecules.
Note: The intermediate after 5-phosphoribosyl-1-amine is called Glycinamide Ribonucleotide (GAR), as glycine is incorporated early on.
- The end product of this complex ten-step pathway is Inosine Monophosphate (IMP).
- IMP contains the complete purine ring structure. It is often referred to as hypoxanthine ribonucleotide.
B. Precursors for the Purine Ring Atoms
The atoms that make up the purine ring come from surprisingly diverse and simple sources. It is helpful to visualize the purine ring and where each atom originates:
- N1: From the amino group of Aspartate.
- C2: From N10-Formyl-Tetrahydrofolate (a folate derivative).
- N3: From the amide group of Glutamine.
- C4, C5, N7: From Glycine (the entire molecule of glycine provides these three atoms).
- C6: From CO₂ (bicarbonate).
- N9: From the amide group of Glutamine.
- C8: From N10-Formyl-Tetrahydrofolate (a folate derivative).
- Two Glutamines
- One Aspartate
- One Glycine
- One CO₂
- Two N10-Formyl-THF (tetrahydrofolate derivatives)
C. Formation of IMP as the Common Precursor
The series of reactions from 5-Phosphoribosyl-1-amine to IMP involves:
- Multiple steps of ATP hydrolysis: Providing the energy for the synthetic reactions.
- Two steps requiring N10-formyl-tetrahydrofolate: Donating single carbon units for the formation of C2 and C8 of the purine ring.
Clinical Relevance: This makes the pathway a target for folate antagonists in cancer chemotherapy (e.g., methotrexate). - Several enzyme-catalyzed reactions: Building up the ring structure sequentially.
D. Conversion of IMP to AMP and GMP
Once IMP is formed, it serves as a branch point for the synthesis of the two major purine ribonucleotides: Adenosine Monophosphate (AMP) and Guanosine Monophosphate (GMP). These two pathways are reciprocally regulated to ensure balanced production.
Synthesis of AMP from IMP
-
Step 1:
IMP is converted to Adenylosuccinate.
- Enzyme: Adenylosuccinate Synthetase.
- Energy Input: GTP is used (hydrolyzed to GDP + Pi). This is a crucial regulatory point: the synthesis of AMP requires GTP, linking the two purine pathways.
- Nitrogen Source: Aspartate is incorporated.
-
Step 2:
Adenylosuccinate is cleaved to AMP and Fumarate.
- Enzyme: Adenylosuccinase.
Synthesis of GMP from IMP
-
Step 1:
IMP is converted to Xanthosine Monophosphate (XMP).
- Enzyme: IMP Dehydrogenase.
- Redox Reaction: NAD+ is reduced to NADH.
-
Step 2:
XMP is converted to GMP.
- Enzyme: GMP Synthetase.
- Energy Input: ATP is used (hydrolyzed to AMP + PPi). This is another crucial regulatory point: the synthesis of GMP requires ATP.
- Nitrogen Source: Glutamine is incorporated.
E. Regulation of IMP, AMP, and GMP Synthesis
The synthesis of purine nucleotides is tightly regulated to match the cell's needs and to maintain a balanced pool of ATP and GTP.
Inhibited by both purine nucleotides (AMP, GMP) and pyrimidine nucleotides.
- Feedback Inhibited by: AMP, GMP, and IMP (the end products of the pathway).
- Activated by: PRPP (substrate availability).
- AMP Synthesis: Adenylosuccinate Synthetase is inhibited by AMP. Its activity is dependent on GTP (linking AMP synthesis to the availability of GMP).
- GMP Synthesis: IMP Dehydrogenase is inhibited by GMP. Its activity is dependent on ATP (linking GMP synthesis to the availability of AMP).
III. De Novo Synthesis of Pyrimidine Nucleotides
We just learned how to make Purines (the double ring). Now, we look at Pyrimidines (the single ring: C, T, and U).
Location: Like Purines, this happens in the Cytoplasm (fluid) of the cell. It is very active in the liver.
A. The Strategy: "Ring First, Sugar Later"
This is the opposite of Purine synthesis.
- Purines: We built the ring directly on top of the sugar (PRPP).
- Pyrimidines: We build the Ring FIRST, and then we attach it to the sugar.
B. The Ingredients (Precursors)
The Pyrimidine ring is simpler. It comes from just 3 sources:
This amino acid provides the bulk of the ring: N1, C4, C5, and C6.
- Glutamine: Provides Nitrogen N3 (Amide group).
- CO₂: Provides Carbon C2.
C. The 6-Step Pathway to UMP
The goal is to make UMP (Uridine Monophosphate). Once we have UMP, we can make all the others.
Step 1: The Committed Step (Rate-Limiting)
Glutamine + CO₂ + 2 ATP → Carbamoyl Phosphate
- Enzyme: Carbamoyl Phosphate Synthetase II (CPS-II).
- Location: Cytosol.
- CPS-I: Mitochondria, uses Ammonia, for Urea.
- CPS-II: Cytosol, uses Glutamine, for Pyrimidines.
Step 2: Formation of Carbamoyl Aspartate
Carbamoyl Phosphate + Aspartate → Carbamoyl Aspartate
Enzyme: Aspartate Transcarbamoylase (ATCase).
This step fuses the pieces together to start the ring.
Step 3: Ring Closure
Loss of water closes the ring to form Dihydroorotate.
Enzyme: Dihydroorotase.
Note: In humans, enzymes 1, 2, and 3 are combined in one big protein called "CAD".
Step 4: Oxidation (The Odd One Out)
Dihydroorotate → Orotate.
Enzyme: Dihydroorotate Dehydrogenase.
⚠️ Important Location Exception:
This is the ONLY enzyme in the pathway located on the Inner Mitochondrial Membrane. All others are in the cytosol. It uses FAD to pass electrons to the electron transport chain.
Step 5: Attachment to Sugar
Orotate + PRPP → Orotidine Monophosphate (OMP).
Enzyme: Orotate Phosphoribosyltransferase (OPRT).
This is the moment the Ring meets the Sugar (PRPP).
Step 6: Decarboxylation
OMP loses CO₂ → Uridine Monophosphate (UMP).
Enzyme: OMP Decarboxylase.
Goal Achieved! We have the first Pyrimidine Nucleotide.
D. Making Other Nucleotides (CTP, dUDP, dTMP)
We have UMP, but we need C, T, and the DNA versions ("d").
We take UTP and add an amino group.
- Reaction: UTP → CTP.
- Enzyme: CTP Synthetase.
- Donor: Glutamine provides the nitrogen. ATP provides energy.
We must remove the oxygen from the Ribose sugar.
- Enzyme: Ribonucleotide Reductase.
- Action: Reduces the OH group at Carbon-2' to just H.
- Requirement: Thioredoxin and NADPH.
3. Making dTMP (Thymine) - Clinical "Hot Spot"
DNA needs Thymine (T), not Uracil (U). We must convert dUMP to dTMP.
The Reaction:
dUMP + Methylene-Tetrahydrofolate → dTMP.
The Enzyme:
Thymidylate Synthase
Cancer cells divide fast and need lots of DNA (lots of Thymine). We can kill cancer by stopping this enzyme.
- 5-Fluorouracil (5-FU): A drug that directly blocks Thymidylate Synthase.
- Methotrexate: A drug that blocks the recycling of the Folate needed for this reaction.
E. Regulation: Controlling the Speed
| Enzyme | Activators (Go!) | Inhibitors (Stop!) |
|---|---|---|
| CPS-II (Step 1) | PRPP, ATP | UTP, CTP (The Products) |
| Ribonucleotide Reductase | Complex regulation to ensure a perfect balance of all 4 DNA blocks (dATP, dGTP, dCTP, dTTP). | |
V. Salvage Pathways for Nucleotides
Concept: "De Novo" synthesis is like cooking a meal from scratch (expensive). "Salvage" is like eating leftovers (cheap and efficient).
A. Why Salvage?
- Energy Saving: De novo synthesis costs 6-7 ATP. Salvage costs only 1 ATP.
- Vital Tissues: The Brain and Red Blood Cells (RBCs) cannot make purines from scratch. They must use salvage pathways to survive.
- Rapid Growth: Bone marrow and immune cells (lymphoid) need so much DNA they use both methods.
B. How Salvage Works
We take a free Base (Adenine, Guanine, etc.) and re-attach it to a sugar (PRPP).
C. Purine Salvage Enzymes
Adenine + PRPP → AMP.
Deficiency: Causes kidney stones (2,8-Dihydroxyadenine stones).
This enzyme does double duty:
- Hypoxanthine + PRPP → IMP
- Guanine + PRPP → GMP
🚑 Clinical Alert: Lesch-Nyhan Syndrome
Cause: Total deficiency of HGPRT.
If HGPRT is missing, the body cannot recycle Purines.
- Waste Buildup: Hypoxanthine and Guanine are degraded into massive amounts of Uric Acid (Hyperuricemia).
- Symptoms: Severe Gout (painful joints), kidney stones.
- Neurological: Severe intellectual disability and Self-Mutilation (biting off lips and fingers).
D. Pyrimidine Salvage Enzymes
This is less critical clinically, but still important.
- UPRT: Salvages Uracil → UMP.
- Thymidine Kinase (TK): Salvages Deoxythymidine → dTMP.
Note: This enzyme is very active in rapidly dividing cells. - Deoxycytidine Kinase (dCK): Salvages Deoxycytidine → dCMP.
VI. Degradation of Purine Nucleotides
What happens to old DNA and RNA? The body must break them down safely.
For Purines (A and G), this process is critical because the final waste product is Uric Acid, which can cause disease if it builds up.
A. The General Strategy
The degradation involves three main phases:
- Dephosphorylation: Removing the phosphate groups (Triphosphate → Monophosphate → Nucleoside).
- Deamination: Removing the Nitrogen (Amino group).
- Oxidation: Turning the remaining ring into Uric Acid.
B. Degradation of AMP (Adenine)
AMP needs to be stripped down to Hypoxanthine.
AMP + H₂O → Adenosine + Pi
Enzyme: 5'-Nucleotidase.
(Alternate path in muscle: AMP Deaminase can turn AMP directly into IMP).
Adenosine + H₂O → Inosine + NH₃
Enzyme: Adenosine Deaminase (ADA)
Inosine + Pi → Hypoxanthine + Ribose-1-P
Enzyme: Purine Nucleoside Phosphorylase (PNP).
C. Degradation of GMP (Guanine)
GMP is stripped down to Xanthine.
- Step 1: GMP → Guanosine (Enzyme: 5'-Nucleotidase).
- Step 2: Guanosine → Guanine (Enzyme: PNP).
- Step 3: Guanine → Xanthine (Enzyme: Guanine Deaminase/Guanase).
D. The Common Pathway to Uric Acid
Both Hypoxanthine (from AMP) and Xanthine (from GMP) meet here. The goal is Oxidation.
The drug Allopurinol (used for Gout) works by inhibiting Xanthine Oxidase. This stops the production of Uric Acid.
E. Characteristics of Uric Acid
- Solubility: It is poorly soluble in water. It likes to turn into crystals (sodium urate).
- Excretion: We pee it out via the kidneys.
- The Danger: If levels get too high (Hyperuricemia), crystals form in joints (Gout) or kidneys (Stones).
- The Good Side: It is actually a strong antioxidant!
VII. Degradation of Pyrimidine Nucleotides
Unlike Purines, Pyrimidine degradation is "clean." The products are water-soluble.
A. The Products
The final products are simple molecules that dissolve easily:
1. Cytosine & Uracil Degradation
They share a pathway. Cytosine is converted to Uracil first.
- Step 1: CMP → UMP (Enzyme: Cytidine Deaminase).
- Step 2: UMP → Uracil.
- Step 3: Ring Opening by DPD (Dihydropyrimidine Dehydrogenase).
- End Product: β-Alanine (Used for Carnosine).
2. Thymine Degradation
Thymine (DNA only) has a methyl group, so its product is slightly different.
- Step 1: dTMP → Thymine.
- Step 2: Ring Opening by DPD.
- End Product: β-Aminoisobutyrate (Excreted in urine).
D. Clinical Relevance: DPD Deficiency
Dihydropyrimidine Dehydrogenase (DPD) is the rate-limiting enzyme for breaking down pyrimidines.
Patients with cancer are often given the drug 5-Fluorouracil (5-FU). This drug mimics Uracil.
The Danger: If a patient has a genetic DPD Deficiency, they cannot break down the drug. The drug builds up to toxic levels, causing death or severe side effects (neurotoxicity, bone marrow failure).
Note: Unlike Purines (Gout), there are no "accumulation diseases" for natural pyrimidines because they are water-soluble.
VII. Regulation of Nucleotide Metabolism
The body must balance these pools perfectly. Too little DNA means cells can't divide. Too much wastes energy.
This section explains the "Traffic Lights" (Regulation) and what happens when the traffic lights break (Disease).
A. General Regulatory Themes
-
🛑
Feedback Inhibition: The product (e.g., AMP) stops its own factory (Enzyme 1).
-
🔄
Reciprocal Regulation: "I'll scratch your back if you scratch mine." Making AMP requires GTP. Making GMP requires ATP. This ensures balance.
-
⚖️
Feed-forward Activation: If ingredients pile up (e.g., PRPP), they push the enzymes to work faster.
B. Regulation of Purine Synthesis
We control the flow at 3 main checkpoints.
- Go: Phosphate (Pi)
- Stop: Any Nucleotide (AMP, GMP, IMP)
Enzyme: Glutamine:PRPP Amidotransferase
- Go: High PRPP
- Stop: AMP, GMP, IMP
- Making AMP: Inhibited by AMP. Needs GTP.
- Making GMP: Inhibited by GMP. Needs ATP.
C. Regulation of Pyrimidine Synthesis
This enzyme makes ALL DNA building blocks (dATP, dGTP, dCTP, dTTP). Its regulation is complex.
- Global On/Off Switch:
ON = ATP (High energy = replicate DNA).
OFF = dATP (Too much DNA precursor = stop). - Fine Tuning: Different dNTPs bind to "Specificity Sites" to ensure the cell doesn't make too much of just one letter (e.g., dGTP stimulates making ADP).
VIII. Clinical Disorders & Pharmacology
1. Gout (Hyperuricemia)
What is it? High Uric Acid leads to sharp crystals depositing in joints (painful arthritis) and kidneys (stones).
- Underexcretion (90%): Kidneys fail to pee it out.
- Overproduction (10%):
- PRPP Synthetase Overactivity.
- High Cell Turnover (Cancer/Chemo).
- Partial HGPRT deficiency.
- Allopurinol / Febuxostat: Inhibits Xanthine Oxidase. Stops Uric Acid production.
- Probenecid: Helps kidneys excrete it.
- Colchicine/NSAIDs: For pain/inflammation.
2. Lesch-Nyhan Syndrome
X-Linked Recessive
Defect: Near total absence of HGPRT (Salvage Enzyme).
- Severe Hyperuricemia: Since purines cannot be salvaged, they are ALL degraded to Uric Acid (Severe Gout in children).
- Neurological (The Hallmark): Spasticity, Mental Retardation, and Compulsive Self-Mutilation (biting lips/fingers).
3. SCID (Bubble Boy Disease)
Adenosine Deaminase (ADA) Deficiency
- Mechanism: Without ADA, Adenosine accumulates. This turns into dATP.
- The Toxic Effect: High dATP turns OFF Ribonucleotide Reductase.
- Result: Cells cannot make DNA. Immune cells (B and T lymphocytes) cannot divide.
- Outcome: Severe Immunodeficiency (Fatal without bone marrow transplant or enzyme therapy).
4. Orotic Aciduria
Defect: Failure of UMP Synthase (OPRT + OMP Decarboxylase).
- Symptoms: Anemia (Megaoloblastic), Growth Retardation.
- Key Sign: Crystals of Orotic Acid in urine.
- Treatment: Oral Uridine. (It bypasses the block and inhibits CPS-II to stop Orotic Acid production).
Pharmacology: Targeting Nucleotides (Chemotherapy)
Cancer cells need nucleotides to grow. We use drugs to starve them.
Inhibits Dihydrofolate Reductase (DHFR). Prevents regeneration of THF (Folate). Stops Thymine and Purine synthesis.
"Suicide Inhibitor" of Thymidylate Synthase. Directly stops DNA from getting Thymine.
Inhibits Ribonucleotide Reductase. Stops conversion of RNA → DNA.
Inhibits De Novo Purine Synthesis (PRPP Amidotransferase).
IX. Additional Clinical & Pharmacological Notes
To complete our study of nucleotides, we must look at a few specific drugs and environmental factors that affect these pathways.
1. Mycophenolic Acid (Transplant Drug)
This is a powerful immunosuppressant drug used to prevent **Graft Rejection** (e.g., after a kidney transplant).
- It acts as a reversible, uncompetitive inhibitor of the enzyme IMP Dehydrogenase.
- Recall: IMP Dehydrogenase is needed to make GMP (Guanine) from IMP.
- The Result: It deprives rapidly dividing T-cells and B-cells of the Nucleic Acids they need to multiply. Without these immune cells, the body cannot attack the transplanted organ.
2. Sulfonamides (Sulfa Drugs)
These are antibiotics. They target bacteria by starving them of Nucleotides.
Bacteria must make their own Folic Acid (Folate) from scratch using a molecule called PABA (Para-aminobenzoic acid).
Sulfonamides look exactly like PABA (Structural Analogs). The bacteria try to use the drug instead of PABA, and their Folic Acid synthesis fails.
Humans cannot make Folic Acid. We must eat it in our diet. Therefore, Sulfa drugs kill bacteria but leave human purine synthesis alone.
3. Lead Poisoning & Gout ("Saturnine Gout")
Historically, Gout was often associated with "High Living" and alcohol. However, there is an environmental link.
- The Cause: In previous centuries, alcohol (especially port wine and moonshine) was often contaminated with Lead during storage or manufacturing.
- The Mechanism: Lead damages the kidney tubules.
- The Result: The damaged kidneys cannot excrete Uric Acid. The Uric Acid builds up, causing Secondary Gout.
4. Dietary Treatment for Orotic Aciduria
We learned that Orotic Aciduria causes Anemia because the body cannot make Pyrimidines (DNA).
Feeding a diet rich in Uridine results in:
- Improvement of Anemia: Uridine can be salvaged to make UMP, bypassing the broken enzyme block. This allows red blood cells to divide again.
- Decreased Orotate Excretion: The Uridine converts to UTP, which feedback-inhibits the first enzyme (CPS-II), stopping the production of the accumulated Orotic Acid.
Biochemistry: Nucleotide Metabolism
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