Nucleotide metabolism

▪ HCl separates the proteins.

▪ Nucleic acids are hydrolyzed by
pancreatic polynucleases.
▪ Intestinal nucleotidases remove
phosphates from nucleotides.
▪ Nucleosides can be absorbed or
more hydrolyzed by the intestinal
nucleases.
▪ The free bases and nucleosides are
catabolized mainly in the liver.
 free purine bases or nucleosides (absorption, degradation or liver synthesis).
Brain cells, RBCs and WBCs (deficient in amidotransferase).

PRPP + Purine → Mononucleotide + PPi

Adenine phosphoribosyl transferase and HGPRTase.

Nucleoside + ATP → Mononucleotide + ADP

Adenosine kinase enzyme.

Ribose-5-P + ATP → PRPP + AMP

PRPP synthase
ATP + Mg+2

PRPP + Glutamine + H2O → 5-Phosphoribosylamine + PPi + Glutamate

PRPP Glutamyl amidotransferase

5-PRamine + 4 ATP + Glycine + 2 THF + Glutamine + CO2 + Aspartate → IMP

IMP + Aspartate + GTP → Adenylosuccinate + GDP + Pi

Adenylate-O-succinate synthase
Adenylosuccinate → AMP + Fumarate
Adenylate-O-succinase

IMP + NAD + H2O → XMP + NADH2

IMP dehydrogenase
XMP + Glutamine + H2O + ATP → GMP + Glutamate + AMP + PPi
XMP Glutamyl Amidotransferase
▪ PRPP.
▪ result nucleotides
(AMP, ADP, GMP & GDP).
They also inhibit Adenyl-O-succinate synthase
and IMP dehydrogenase enzymes.

▪ Activity of PRPP synthase is feedback

regulated by AMP, ADP, GMP and GDP.
▪ Activity of PRPP glutamyl amidotransferase
is feedback regulated by GMP and AMP.
 Uric acid, which is excreted in urine (500 mg/day).
4-7 mg/dl.
▪ In lower mammals, uric acid is oxidized into allantoin
(highly water soluble) by uricase enzyme.
▪ Mutase converts ribose1-P into ribose5-P.

Azaserine: inhibitor of amidotransferase enzymes.

Methotrexate & trimethoprim.
Inhibitors of folic acid synthesis (analogue to PABA).
Inhibitor for RNA synthesis.
Inhibitor of viral DNA synthesis (anticancer).
Inhibitor of purine synthesis (structurally analogue to IMP).
Inhibitor of ribonucleotide reductase (anticancer).
Xanthine oxidase inhibitor (oxy-purinol).
CO2 + Glutamine → Carbamoyl-P + Glutamate.
cytosolic carbamoyl phosphate synthase II.
2ATP → 2ADP + 2Pi

Carbamoyl-P + Aspartate → Carbamoyl Aspartate + Pi.

Aspartate Transcarbomylase.
Carbamoyl Aspartate + H2O → Dihydro-Orotate.
Dihydro-Orotase.
Dihydro-Orotate + NAD → Orotate + NADH2.
DHO dehydrogenase (mitochondrial enzyme).
Orotate + PRPP → OMP.
Orotate PR transferase.
OMP → UMP + CO2.
OMP decarboxylase.
Formation of UTP:
2 Kinases (ATP utilizer).

UTP + Glutamine → CTP + Glutamate

: CTP synthase.
UMP + NADPH2 → dUDP + NADP
: Ribonucleotide reductase.
dUDP + H2O → dUMP + Pi
dUMP + Methylene FH4 → TMP + FH2
: Thymidylate synthase.

--- by UTP and +++ by PRPP & ATP.

--- by CTP and +++ by ATP.
--- by CTP.

Uridine/Cytidine kinase, Thymidine Kinase, Deoxy Cytidine kinase, OPRT.

ATP.

CO2, NH3, β-Alanine and β-amino isobutyrate.

 1) ↑ PRPP synthase (resistance to allosteric inhibition by purine).
2) ↓HGPRTase (Lesch Nyhan syndrome).
3) ↓Glucose-6-phosphatase (Von Gierke's disease).

4) ↑cell division rate and tissue turnover (cancer).

It increases the destruction of nucleic acids.
5) ↓ renal excretion of uric acid (renal failure, some diuretics or lead poisoning).

↑insoluble urate → crystallization and deposition

of Na urate in soft tissues and joints.
small joints especially those of big toes.

Deposition of urate crystals in renal tubules → kidney stone.

1) Restriction of animal protein diet [red meat, liver, kidney).

2) Allopurinol, competitive inhibitor for xanthine oxidase.
Uric acid level in blood is lowered while xanthine and hypoxanthine
are elevated (water soluble and easily excreted in the urine).
3) Colchicine; inhibits Phagocytosis of urates so decreases the acute pain.

rare
xanthine oxidase deficiency due to either genetic defect or severe liver damage.
excessive excretion of xanthine and hypoxanthine (rare xanthine renal stones).

▪ AMP accumulation → dAMP → dATP accumulation → allosteric inhibition

of reductase enzyme → ↓ deoxy nucleotides → ↓ DNA synthesis.
SCID → impaired growth due to recurrent infections (death within two years).

deficiency of OPR-Transferase (Type I) or OMP Decarboxylase (Type II).

anemia, growth retardation, increased Orotic acid in blood and urine.
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 Urinary calculi
Urinary stones composed of substances normally excreted in the urine.
These substances are supersaturated, precipitated and form crystals.
The crystals are then bound together by a binding substance forming stone.
Urinary stones may be simple (one constituent) or mixed stone (two or more constituents).

1. Calcium oxalate.
2. Calcium phosphate.
3. Calcium carbonate.
4. Magnesium ammonium phosphates (triple phosphate).
5. Less commonly stones are formed of: Uric acid, cystine or xanthine stone.

1) Alkaline urine pH: due to the action of bacteria on urea in UTI.

Alkalinity causes precipitation of crystals and stone formation.
2) Disturbance in vitamins:
A. Excess vitamin D: calcium stone.
B. Excess vitamin C: oxalate stones.
C. Deficient vitamin A: roughness of the urinary epithelium.
3) Disturbance in hormones (hyperparathyroidism): calcium stones.
4) Excess excretion of uric acid (gout): uric acid stones.
5) Excess excretion of cysteine (cystinuria): cystine stones.
6) Excess mucoprotein in urine: cement that binds the salts to form a stone.

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 Minerals metabolism

Table salt mainly. Table salt mainly. Vegetables, fruits, grains,

meat, milk, legumes, coconut.
In the ileum In the ileum Mainly in the jejunum
(Cotransport). (Passive diffusion). (Passive diffusion).
Na/K pump: Na/K pump:
1) OP …….
1) Nerve transmission. 2) Nerve transmission.
2) Muscle contraction. 3) Muscular & cardiac activity.
2) Activation of
3) Acid-base balance. 4) Acid-base balance.
amylase enzymes.
4) Osmotic pressure and 5) rotein biosynthesis.
3) Formation of HCl in
ECF & plasma volume. 6) Cofactor of yruvate
the stomach.
5) Regulation of ABP. kinase.
135-145 mmol/L 96-106 mmol/L. 3.5- 5 mmol/L.
The main extracellular The main extracellular The main intracellular cation
cation (2/3 body sodium). anion. (98% of body potassium).
Mainly in urine and sweat Mainly in urine. Mainly in urine (less in feces
(95%). & sweat).
5 g/day. 5 g/day. 4 g/day.

Total body K is influenced by age, sex and muscle mass (most of body K is found in muscles).
Factors affecting plasma sodium: Aldosterone, RAAS, GFR, RBF, ANP.
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1) Cushing syndrome: excess corticoids. 1) Addison's disease: less aldosterone.
2) Conn's disease: excess aldosterone. 2) Renal failure: impaired reabsorption.
3) Diabetes insipidus: less ADH (water loss). 3) Hypotonic dehydration: ttt by water.
4) Drugs: ACTH or cortisone. 4) Drugs: thiazide.

1) Cushing disease: excess corticoids. 1) Addison’s disease: less aldosterone.

2) Conn's disease: excess aldosterone. 2) Renal failure: low GFR and Oliguria.
3) Renal loss: disease or diuretics. 3) Acidosis: due to shift of K+ to
4) GIT loss: vomiting or diarrhea. extracellular in exchange with H+.
5) Alkalosis: due to shift of potassium from 4) Necrosis (trauma, malignancy and
the ECF to the ICF. burns): leakage of tissue potassium.
6) Treatment of hyperglycemia by insulin 5) IV fluids with excessive potassium salts.
without potassium. 6) Uncontrolled DM: ↓ insulin associated
acidosis prevents K+ from entering cells.
1) Anorexia, nausea, vomiting. 7) Diabetic coma, severe dehydration.
2) Muscle cramps, or tender ness.
3) ECG changes. Cardiac arrest, arrhythmia and ECG changes
4) Polyuria, polydipsia. with muscle weakness.
5) Lethargy and confusion. > 6.5 mmol/L.

Renal tubular acidosis and hyperventilation. Intestinal obstruction and excess vomiting.
Loss of HCO3- in exchange with Cl-. Reabsorption of HCO3- in exchange with Cl-.

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 Metabolism of water
The major body constituent that influences the structure and function of the cell.
1. Solvent for ions and neutral molecules (medium for biochemical reactions)
2. Strong dissociation of macro molecules.
3. Regulation of body temperature.
4. Vehicle for transport of solutes.
42L (60% of 70kg normal adult male).
A. ECF: 14L (20% of body weight).
B. ICF: 28L (40% of body weight).

A. Exogenous sources: ingested water, beverages and water content of solid food.
0.5–5 L/day (according to social habits and climates).
B. Endogenous sources: metabolic water produced by food oxidation (300-350 ml/day).
Water ingestion is controlled by thirst center in the hypothalamus in the third ventricle.
It is stimulated by ECF hyper-osmolality and hypovolemia and vice versa.
Urine (major route), skin, lungs or feces.
Daily urine output (1-2 L/day) is balanced according to fluid intake or diseases.
The human body can’t stop the production of urine even if water intake is nil.
Additional water loss:
1) Kidney diseases.
2) Diarrhea and vomiting especially in infants.
3) Excessive sweating in fever and high environmental temperature.

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 There is no water reserve in the body.

▪ ECF: ↓ volume, ↑osmolality, ↑ electrolyte (Na).

Plasma protein (Normal or slightly increased) and urea (slightly increased).
▪ Cells: Shrunken and disturbed metabolism (↑protein breakdown).
▪ Urine: Oliguria, ↓Urine sodium due to ↑ ADH secretion.
Oliguria, dry tongue, thirst, hemoconcentration, muscle weakness and confusion.
a state of pure water excess or water intoxication.

1) Excessive intake of salt free fluids.

2) Excessive administration of IV fluids.
3) Renal failure or Hypersecretion of ADH.

Headache, Confusion, Convulsion. Muscular weakness or lethargy.

Nausea, Vomiting. Coma and Death.

▪ ECF: ↑ volume, ↓ osmolality, ↓ plasma Na, ↓ plasma proteins.

▪ Urine: Polyurea with ↑ urine sodium except in Addison’s disease.

A. Restriction of water intake.

B. Infusion of hypertonic saline.

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 Physical chemistry
solutions in which the size of particles is less than one nanometer.
solutions in which the size of particles ranges from one to 200 nanometers.
solutions in which the size of particles is more than 200 nm.
separation of colloids from crystalloids using a semi permeable membrane.

Crystalloids can pass through the semi-permeable membrane.

Colloids cannot pass through it due to its large size (molecular weight).
A mixture of proteins and salts can be separated using a semi-permeable membrane.
renal dialysis
In renal failure, the blood passes through a dialyzing machine to get rid of crystalloid
waste products and preserving the colloidal plasma proteins.
the passage of solvent molecules from lower to higher concentration
through a semi-permeable membrane.
The semi-permeable membrane contains certain pores that allows the passage
of small particles (solvent) and prevents passage of large particles (solutes).
the hydrostatic pressure needed to prevent osmosis.

1) Number of dissolved particles: Crystalloids have a higher osmotic pressure.

2) Number of ions (ionization): lonizable molecules have a higher osmotic pressure.

1) Urine formation:
Inside the glomerular capillaries, there are 2 Opposite forces:
Filtration force: + 35 mm Hg (caused by capillary blood pressure).
Reabsorption force: - 20 mm Hg (caused by osmotic pressure).
The net filtration pressure = +35 - 20 = + 15 mm Hg.
In shock: ↓ BP → filtration stops → anuria until blood pressure is restored.
2) Formation and reabsorption of interstitial fluid:
ISF is formed by plasma filtration at the arterial end of the blood capillaries.
It is reabsorbed by plasm osmotic pressure at the venous end.
3) Hemolysis:
Isotonic solution (0.9% saline) has the same osmotic pressure of RBCs (neither swell nor shrink.)
Hypertonic solution has a higher osmotic pressure than RBCs (lose water and become crenate).
Hypotonic solution has a lower osmotic pressure than RBCs (absorb water, swell and hemolysis).
the fluid resistance to flow due to the internal friction between its molecules.
Temperature, solute concentration and size.
Viscosity of the blood is due to plasma proteins, RBCs and WBCs.
It affects blood pressure (↓in anemia and hypoproteinemia but ↑in polycythemia).
 the force which holds (attract) the surface molecules of a liquid together.
the breakdown of large fat globules in water into small ones.
lower the surface tension of water e.g. bile salts, soap and proteins.

Acid-base balance
1) The buffer systems (Chemical regulation):
It minimizes the changes in pH within less than one second.
2) The respiratory system (Physiological regulation):
It restores about 2/3 pH changes within 1-10 minutes.
3) The kidneys (Physiological regulation):
It restores pH to its normal level within 12-24 hours (the most powerful).

▪ In respiratory acidosis (↓HCO3/CO2 ratio):

PCTs (80-90%), thick ascending limb of loop of Henle and CDs.

It returns back to the blood to restore the alkali reserve.

PCTs, thick LH and early DCTs: Late DCTs and CDs:

ry
2 active counter transport in 1ry active counter transport in I cells
exchange with Na+ reabsorption. (H+ transprotein ATPase).
Only a small part of the excess H+ can be excreted in its ionic form in urine.
The rest of it is excreted by their combination with buffers in the tubular fluid
such as phosphate buffer and ammonia buffer.