Biochemistry of Disease:

Biochemistry of Disease

All Diseases Have a Biochemical Basis:

-Life as we know it on earth depends upon biochemical reactions.

-If they cease, death results.

-Health: is defined as "the harmonious functioning of thousands of biochemical reactions and processes that occur in normal cells and that operate to maintain homeostasis (constancy) of the internal environment".
-Disease: results from perturbations of structures, i.e. DNA in genetic diseases amounts, of certain biomolecules perturbations, of important biochemical reactions and processes.

Six Points Regarding Disease From a Biochemical Standpoint:

[1] Many diseases are determined genetically.

[2] All classes of biomolecules found in cells are affected in structure, function or amount in one disease or another. Biomolecules can be effected in a primary or secondary manner.

Involvements of Various Biomolecules in Disease:

Biomolecule	Property Affected	Disease	Fundamental Cause
DNA	Structure	Sickle Cell Anemia	Mutation
RNA	Structure	Thalassemia	Mutation (faulty splicing mRNA)
Protein	Structure / Function	Sickle Cell Anemia	Mutation
Lipid	Amount	Tay-Sachs	Mutation
Polysaccharide	Amount	Glycogen Storage	Mutation (gene for Glycogen Phosphorylase)
Electrolyte	Amount in Sweat	Cystic Fibrosis	Mutation (membrane protein affecting transport of Cl-)
Water	Amount	Cholera	Infection (bacterial, small intestine)

[3] Biochemical perturbations that cause disease may occur rapidly or slowly.

[4] Diseases can be caused by deficiency or excess of certain biomolecules.
[5] Almost every cell organelle has been involved in the genesis of various diseases.

Involvements of the Major Intracellular Organelles in Various Diseases:

Organelle Disease(s) Mechanism

Organelle Disease(s) Mechanism

Nucleus Most genetic diseases Mutations in DNA

Mitochondria Hereditary myopathies Mutations in DNA affecting the structure of proteins (i.e. NADH DH)

ER Chemical toxicities Enzymes like Cytochrome P-450 can activate various compounds to potentially toxic species

Golgi I-cell disease Absence of a phosphotransferase resulting in lysosomal enzymes being misdirected and secreted by affected cells

Plasma Membrane Metastasis of cancer cells Changes in the oligosaccharides of glycoproteins

Lysosome Lysosomal storage disease Decreased activity (due to mutations) of various hydrolases result in accumulation of certain biomolecules

[6] Different biochemical mechanisms can produce similar pathologic, clinical and laboratory findings.

The Major Pathologic Processes by Which the Body Reacts to Disease-Causing Perturbations:

Pathologic Process	One Cause	Disease	Biomolecule(s) Involved
Inflammation, acute or chronic	Infection, bacterial or viral	Pneumonia	PG's and LT's
Degeneration	Various Chemicals	Fatty Liver	Ethanol
Organ Enlargement	Accumulation of certain compounds	Gaucher's Disease (enlarged liver and spleen)	Glucosylceramide
Anemia	Lack of Vitamin	Iron Deficiency Anemia	Iron
Neoplasia	Irradiation	Leukemia	DNA Damage
Cell Death	Diminished blood supply	MI	Lack of Oxygen
Fibrosis	Follows cell death	Cirrhosis of the Liver	Accumulation of Collagen
Calculus	High local concemtrations of certain compounds	Gout	Uric Acid

Genetic Diseases:

-The molecular basis of most genetic diseases will be revealed within the next decade.

-Genetic diseases account for about 10% of hospitalized children and many of the chronic diseases that afflict adults (i.e. diabetes, atherosclerosis).

-The successful sequencing of the human genome has major implications for the study of health and disease.

Successful treatment for Some Genetic Diseases:

Three Strategies:

(1) Administration of the missing product or limiting the availability of substrate.

(2) Replacement of an absent enzyme or protein.

(3) Removal of excess of a stored compound.
(4) Direct attempts to correct the basic genetic abnormality.

Strategy	Principle	Disease	Treatment
1	Replace Product	Goiter	Administration of 1-Thyroxine
1	Limit Substrate	PKU	Diet low in Phe
2	Replace Enzyme	Gaucher's	Injections of b-glucosidase
2	Replace Protein	Hemophilia	Injections of Factor VIII
3	Supply Co-Factor	Aciduria	Injections of Vitamin B-12
4	Replace Organ	Galactosemia	Liver Transplantation
4	Gene Therapy	Many	Adenosine Deaminase Deficiency

Organelle	Disease(s)	Mechanism
Nucleus	Most genetic diseases	Mutations in DNA
Mitochondria	Hereditary myopathies	Mutations in DNA affecting the structure of proteins (i.e. NADH DH)
ER	Chemical toxicities	Enzymes like Cytochrome P-450 can activate various compounds to potentially toxic species
Golgi	I-cell disease	Absence of a phosphotransferase resulting in lysosomal enzymes being misdirected and secreted by affected cells
Plasma Membrane	Metastasis of cancer cells	Changes in the oligosaccharides of glycoproteins
Lysosome	Lysosomal storage disease	Decreased activity (due to mutations) of various hydrolases result in accumulation of certain biomolecules