Basic protein structure
Proteins come in several shapes:
alpha helix: a long spiral that is stabilized by hydrogen bonds. These proteins often go across membranes. A mutation that substitutes an incompatible proline amino acid will disrupt this structure.
beta pleated sheet: side-by-side arrays of proteins strands are held together by hydrogen bonds. Best example is the protein known as amyloid
beta bonds: a key component of globular proteins that have many glycine amino acids which allow complex folding to occur
Globular proteins that are in circulation, such as immunoglobulins (antibodies), have their hydrophobic bonds located within the folded structure, and which along with stabilizing disulfide bonds, help them maintain their structure in circulation
Cell wall proteins have their hydrophobic bonds on the outside, similar to the lipid bilayer of the cell membrane
Fibrous proteins provide structure, especially to connective tissues.
Collagen is the best known structural protein. It is a globular protein with a triple helix configuration. It has lots of hydroxyproline and hydroxylysine residues that stabilize the structure. Procollagen is made within the cell cytoplasm (such as a fibroblast) and secreted to the extracellular compartment where it is cleaved to collagen. Collagen is like rope.
Abnormal collagen is produced with vitamin C deficiency (scurvy) because the pro-alpha chains that form the triple helix are not properly hydroxylated
Abnormal collagen (type 1) is formed with the inherited disorder osteogenesis imperfecta, leading to abnormal bone matrix and fractures
Abnormal collagen (type 1) with Ehlers-Danlos syndrome leads to hyperflexible joints
Elastin is a specialized connective tissue protein that acts like a rubber band, giving elasticity to tissues such as lung (which expands and contracts) and skin, which moves when you do (burn injuries destroy elastin, which is not regenerated)
Keratin is a protein with lots of cysteine with lots of disulfide bonds that makes it tough and insoluble for protection in the epidermis and nails, so you don't melt in the shower.
Proteases are produced in the process of inflammation. Neutrophils are good sources of proteases, and they are constantly being activated, so the body needs a circulating anti-protease, such as alpha-1-antitrypsin (AAT), to oppose this effect. Persons with AAT deficiency have lung damage and emphysema, or liver damage and cirrhosis.
Hemoglobin
Hemoglobin is composed of heme and globin chains. Each heme molecule consists of a protoporphyrin containing a ferrous ion (Fe++). Normal adult hemoglobin has 2 alpha globin chains and two beta globin chains. Each globin chain has a heme group.
Myoglobin has one globin chain and one heme group. It is found in striated muscle. It has a higher affinity for oxygen than hemoglobin.
The oxygen dissociation curve governs the binding and release of oxygen from hemoglobin.
A high oxygen tension in the lung, coupled with a high pH (from CO2 delivered to the lung by venous blood), favors oxygen binding and release of CO2 (Bohr effect). The reverse happens in the tissues. When oxygen binds to iron in heme, there is allosteric interaction to modify the quaternary structure, which increases affinity for subsequent oxygen binding. This favors loading of all hemes with oxygen in the lung and off-loading of the last oxygen in tissues. This allosteric interaction accounts for the sigmoidal dissociation curve.
Most CO2 is bound and buffered in the blood by the HCO3 found within RBCs. This is why attempt to make fake blood substitutes out of fluorocarbons, which only carry oxygen and do not act as a buffer, don't work well.
The affinity of hemoglobin for carbon monoxide is 200 times that of oxygen, which is why even small amounts of CO in the environment are dangerous.
RBCs, powered by glycolysis, turn glucose into lactate, with the production of the intermediate 2,3 BPG. A buildup of 2,3 BPG shifts the oxygen dissociation curve of hemoglobin to the right, releasing more oxygen at a lower pH under conditions of hypoxia when glycolysis is prominent. Blood collected for transfusion has inosine added which goes to the HMP shunt and into 2,3 BPG production.
Hemoglobin F in babies has a higher oxygen affinity to favor oxygen transfer across the placenta to the fetus. Hgb F binds more weakly to 2,3 BPG.
Thalassemias are inherited disorders of globin chain production. There are alpha and beta thalassemias. Affected persons can have anemia and excess iron absorbtion from increased erythropoiesis. Fetuses with no alpha globin chains (severe alpha thalassemia is seen in Southeast Asia) have hydrops and are usually stillborn.
Sickle cell anemia (Hgb S) is due to a point mutation in the beta globin chain with substitution of valine for glutamate at position 6. Biochemists are very proud of this discovery, because beta globin was one of the first proteins sequenced. There are plenty of beta globin chains, but the Hgb S is not stable at low oxygen tension and causes the RBC to change shape (sickle).
Methemoglobin results from oxidation of the Fe++ to Fe+++, which does not bind oxygen well. Some oxidizing drugs have this effect. There is hemolysis (breakdown and lysis of RBCs) and production of brown urine.
The diseases known as the porphyrias involve abnormalities of heme production with increased porphyrins. The prototype is acute intermittent porphyria, with photosensitivity and avoidance of sun exposure, red urine from hemolysis, odd behavior, and abdominal pain (the legend of the werewolf may be based upon porphyria).
Old RBCs are recycled, with breakdown of the heme to bilirubin, mainly in the liver and spleen. The iron from the heme is recycled into iron stores and re-used in the marrow. Iron is transported by transferrin in the blood and stored as hemosiderin in tissues. The serum ferritin (a storage form that circulates) gives an indication of the amount of iron stored. With iron deficiency anemia, the RBCs are fewer and smaller (microcytic anemia).
Bilirubin that has not been metabolized in the liver is called unconjugated bilirubin (indirect bilirubin, as measured in the blood) and is increased greatly with hemolysis of RBCs.
The liver conjugates the bilirubin with glucuronic acid and excretes it into bile. Bile passes down the biliary tract into the intestine, where the glucuronic acid is removed and bilirubin is converted to urobilinogen, which is then metabolized by bacteria to stercobilin to make stool appear brown or oxidized to urobilin. Conjugated bilirubin appears as "direct" bilirubin in the blood.
Light-colored ("clay colored") stools mean that there is probably liver or biliary tract disease.
Hyperbilirubinemia results from liver disease (example: hepatitis) or biliary tract disease (example: gallstones) or hemolysis (example: sickle cell anemia). The affected patient has icterus (jaundice).
Enzymes
Proteins acting as enzymes have a complex folded structure with an active site, a pocket into which a specific substrate will fit. Enzymes typically need a metal ion cofactor (which is why trace minerals in the diet such as zinc are important).
Enzyme action is affected by pH, substrate concentration, temperature, and inhibitors. A small Km means that the enzyme has a high affinity for the substrate. Enzymes can be affected by competitive and noncompetitive inhibition.
A competitive inhibitor binds at the active site, with an effect reduced by increased substrate. A plot of enzyme activity with competitive inhibition shows a lowered curve. Many chemotherapy agents are competitive inhibitors because they bind only to the active site and increase the Km.
A noncompetitive inhibitor does not bind at the active site, so changes in substrate concentration have no effect on the inhibitor. A plot of enzyme activity with noncompetitive inhibition shows an increased straight line slope.
Enzymes have some specificity for different tissues, which makes them useful laboratory markers because they are released into the blood when those tissues are injured:
CPK (CK): striated muscle (MB fraction in heart; MM in skeletal muscle)
AST (SGOT): liver, RBCs, muscle
ALT (SGPT): liver
LDH: lots of tissues, including muscle, liver, kidney
Amylase and lipase: pancreas
Protein kinases are control enzymes that catalizy phosphorylation of another enzyme to increase or decrease its activity.
Inherited disorders of enzymes generally appear as autosomal recessive conditions, because half of the enzyme is generally enough to provide sufficient function.
Cellular Energy Production
Mitochondria are the powerhouses of the cell.
The inner matrix has the enyzmes needed for oxidation, and the electron transport chain is located on the inner membrane.
NAD+ is reduced to NADH on the electron transport chain. Coenzyme Q accepts hydrogen ion. Cytochromes have porphyrin with heme (reversible from Fe++ to Fe+++)
The proton pump is powered by electron transport. Omeprazole is a drug that inhibits the proton pump to decrease gastric acid (from hydrogen ion) production.
Mitochondria have their own genome with a single circular strand of DNA with about a dozen genes coding for proteins involved in oxidative phosphorylation. Mutations in these genes (passed from mother to offspring) lead to mitochondrial myopathies with muscle and CNS dysfunction appearing in childhood to middle age.
Intracellular Messengers
Adenylate cyclase is a second messenger becoming active when there is binding of a messenger, such as a hormone, to a cell surface membrane receptor. This binding triggers activation of adenylate cyclase.
Conversion of ATP to cAMP by adenylate cyclase may be GTP dependent.
cAMP may require a protein kinase for activation.
Neurotransmitters and hormones act via binding to cell surface receptors. Such binding may trigger another reaction-activation of phospholipase C, which can:
produce inositol 1,4,5 triphosphate that releases calcium ion (Ca++)
produce diacylglycerol that activates protein kinases
Calmodulin in the cell regulates these effects
cGMP can be found in platelets and participates in activation of platelet aggregation to form a clot.
Nitric oxide (NO) is a messenger that is produced in cells with nitric oxide synthase (NOS). NO produced by endothelium causes smooth muscle relaxation and vasodilation, while NO produced in macrophages helps kill micro-organisms.
Glycolysis
Glucose must be transported into cells by glucose transporters (GLUTs) under control of insulin. Mesenchymal tissues (muscle, fat, connective tissues) require insulin to get glucose into their cytoplasm. Many cells, such as those in nervous system, kidney, and liver, do not.
Glucose is phosphorylated by:
hexokinase, with a high affinity for glucose, and is widely distributed in tissues
glucokinase in liver and pancreatic beta cells in islets, with a lower affinity, so the glucose level must be high, which is part of the regulatory mechanism of insulin production by beta cells in the pancreatic islets
Eating increases blood glucose, increasing insulin, which increases cell glucose uptake and production of fructose 2,6 BP, with decreased PFK, which increases glycolysis and decreases gluconeogenesis
Fasting decreases blood glucose, decreasing insulin but increasing glucagon, which decreases fructose 2,6 BP which leads to decreased glycolysis and increased gluconeogenesis
With diabetes mellitus type I, there is an absolute lack of insulin, so hyperglycemia results. The body uses proteins (catabolism) and fatty acids (with resultant ketoacidosis) as an alternative energy source.
With diabetes mellitus type II, there is an increased peripheral cell resistance to insulin, so blood glucose rises.
With glycolysis, there is production of 2 ATP per glucose. If oxygen tension is low, then anaerobic glycolysis occurs, with formation of lactate from pyruvate. In conditions of hypoxia and/or poor tissue perfusion, the blood lactate rises. Lactate can be converted back to glucose in the liver.
If the enzyme pyruvate kinase is absent from mutation (pyruvate kinase deficiency), then RBC glycolysis is affected and hemolysis occurs.
If myophosphorylase is missing, then there is no anaerobic glycolysis in skeletal muscle and the blood lactate does not rise with exercise. This is known as McArdle's disease, a form of glycogen storage disease, in which young persons note muscle pain and cramping with strenuous exercise.
Krebs Cycle
Within the mitochondria, the citric acid cycle (Krebs cycle) oxidizes acetyl CoA to carbon dioxide and water. 12 ATPs are produced per acetyl CoA oxidized. The actual yield of ATP per glucose is less than the theoretical yield.
Alpha-ketoacids (pyruvate, oxaloacetate, alpha-ketoglutarate) derived from glycogenic amino acid metabolism can enter the citric acid cycle.
Conversion of pyruvate to acetyl CoA by pyruvate dehydrogenase is irreversible.
Two of the histochemical stains used to check for healthy skeletal muscle fibers on a biopsy are NADH and succinic dehydrogenase, key parts of the citric acid cycle
HMP Shunt
This pathway produces NADPH which is an important reducing agent that helps generate glutathione that is an antioxidant that protects cells against free radical oxidants that are being generated (more so under conditions of inflammation or hypoxia).
NADPH is needed by the cytochrome p-450 system in liver that hydroxylates steroids and metabolizes many drugs.
Mutations that decrease NADPH oxidase that is involved in the "respiratory burst" of neutrophils to generate superoxide that is involved in generation of free radicals lead to decreased bactericidal activity and to a disease called chronic granulomatous disease.
The X-linked disorder known as G6PD deficiency leads to reduced NADPH production. The RBCs are oxidized and hemolyzed, particularly when the affected person takes an oxidant drug such as an antimalarial compound. This disorder is more common in African-Americans.
How Sweet it Is (Sugars)
Disaccharides (digested to simple sugars in the small intestine) are common in the diet and are typically:
Sucrose is a combination of glucose and fructose (this is table sugar). Sucrose is never seen in the blood and is not tested for.
Lactose is a combination of glucose and galactose (this is milk sugar). Lactose is never seen in the blood and is not tested for.
Lactose intolerance occurs with decreased beta-galactosidase (lactase), leading to bloating and diarrhea when milk products are ingested in adults (babies and children have another way of digesting lactose). The undigested lactose is happily devoured by gut bacteria.
Lack of fructokinase leads to fructosuria which causes an osmotic diuresis (the sugar pulls water with it) with dehydration.
Lack of aldolase B leads to increased intracellular fructose that damages hepatocytes, leading to liver failure with hypoglycemia, jaundice, and coagulation defects.
An inherited disorder with diminished glucose-1-phosphate
galatose-1-phosphate uridyltransferase leads to to galactosemia which causes liver, CNS, kidney, and eye damage. There is marked liver fibrosis with fatty change starting in infancy. This condition is tested for at birth.
Prolactin stimulates N-acetyllactosamine production in the breast after delivery to promote milk production with lactose
Glycogen Storage Diseases
There are several types. They are enzymic defects that affect the breakdown of glycogen, leading to an accumulation of glycogen, mainly in liver, kidney, and muscle. The most characteristic are:
Type I (vonGierke's disease): glucose-6-phosphatase deficiency. Liver and kidney mainly affected. Leads to hepatocyte damage with enlarged, fatty liver. Affected person must eat frequently to avoid hypoglycemia.
Type II (Pompe's disease): lysosomal alpha-glucosidase deficiency. liver and heart affected. There is marked cardiomegaly with heart failure in infancy and early childhood.
Type V (McArdle's disease): myophosphorylase deficiency with muscle cramping and pain.
Glycosaminoglycans - Mucopolysaccharidoses
These are complexes of polysaccharide and protein that are found mainly in intercellular ground substances in connective tissues: hyaluronic acid, chondroitin sulfate, dermatan sulfate, etc.
Lack of degradation enzymes in lysosomes leads to abundance of precursors and another form of storage disease. These are known as the mucopolysaccharidoses.
The prototype is Hunter-Hurler syndrome (which is the only X-lined form, the rest are autosomal recessive). There is CNS damage, abnormal facial features, and eye problems. The features appear in childhood.
Lipids
Lipid digestion is dependent upon:
Bile production with bile salts that function as an emulsifier. Biliary tract disease (cholecystitis, gallstones) can affect bile salt production and circulation. Bile salts are recycled and may be lost with terminal ileal disease.
Pancreatic lipase production. Pancreatic disease, such as pancreatitis or cystic fibrosis, can affect lipase production.
Enough small bowel to absorb the lipids
Malabsorbtion of lipids leads to steatorrhea (diarrhea with foulsmelling stools)
Malabsorbtion of fats leads to potential deficiencies of the fat soluble vitamins A, D, E, and K.
Lipids absorbed in the bowel are mostly assembled into chylomicrons for transport to the liver. Chylomicrons contain glycerol, cholesterol components, and phospholipids complexed with transport apoproteins. Chylomicrons circulate in the blood. Endothelial lipoprotein lipase splits off fatty acids that go to adipose tissue and muscle. Cholesterol-rich remnants go to liver. From the liver, chylomicrons are processed to smaller components that go elsewhere. Very low density lipoproteins (VLDL) from liver are transformed in adipose tissue and muscle to low density lipoprotein (LDL) cholesterol which is then taken up by a variety of cells with LDL receptors that need cholesterol for membrane synthesis.
About a third of LDL is degraded (oxidized) to to a form that can be taken up by macrophages and cells with modified LDL receptors (arterial walls), and this is what drives atherosclerosis.
HDL cholesterol helps transport chylomicron remnants away away from vessels.
Familial hypercholesterolemia is a disorder exhibiting dosage sensitivity. Inheritance of one bad gene means a 50% reduction in LDL cholesterol receptors and resultant hypercholesterolemia in the range of 300 to 400 mg/dL. The rare homozygous state leads with virtual absence of receptors leads to cholesterols above 600 mg/dL and severe atherosclerosis early in young adulthood.
The very rare disorder of familial lipoprotein lipase deficiency leads to hyper chylomicronemia. Chylomicrons also accumulate in the disorder abetalipoproteinemia in which a carrier apoprotein is absent.
Eating lots of saturated fatty acids (found in animal fat) is bad for you because this promotes atherosclerosis. Eating monosaturated fats (olive oil) or unsaturated fats (vegetable oils such as safflower oil) is good for you.
It is better to eat a diet with less than 30% fat, with less cholesterol. However, you make endogenous cholesterol that is regulated in part by HMG CoA reductase. This enzyme is inhibited by all the popular "statin" drugs (simvastatin, lovastatin, etc) that help to reduce serum cholesterol by upregulating LDL receptors.
Many mediators of inflammatory reactions are produced by the arachidonic acid pathway that releases the substrate arachidonic acid from cell membrane phospholipids.
The cyclo-oxygenase (COX) pathway produces prostaglandins that cause pain, vasoconstriction, and smooth muscle contraction. Drugs such as aspirin and NSAIDS block this pathway. Prostaglandins produced with intrauterine infection lead to abortion. There are two isoenzymes of cyclo-oxygenase - COX1 and COX2. COX 1 is present in all cells, while COX 2 has to be induced and is part of an inflammatory response. Drugs such as celecoxib which are selective COX2 inhibitors theoretically have a more focused anti-inflammatory action.
Platelets produce thromboxane to promote aggregation and clotting
Endothelial cells produce prostacyclin wto reduction platelet function and resist clotting.
The lipo-oxygenase pathway produces leukotrienes that can cause bronchoconstriction and leaky blood vessels. Some anti-asthma drugs block this pathway.
When there is not enough glucose available to cells (in type I diabetics, not enough insulin to promote glucose uptake) then cells begin to metabolize fatty acids and produce ketone bodies (acetone, acetoacetate, beta-hydroxybutyrate).
This leads to ketosis, with acidosis (ketoacidosis). Affected persons are very ill and have a fruity odor (like juicy fruit gum) to their breath, are hyperventilating (to compensate with respiratory alkalosis), and may become comatose.
Phospholipids are metabolized to phosphatidyl choline and phosphatidyl glycerol in the lung by type II pneumocytes, forming lamellar bodies that contain the surface tension lowering agent surfactant. Surfactant helps keep the lungs expanded. Babies born prematurely do not have enough surfactant and develop respiratory distress with hyaline membrane formation in alveoli.
Glycosphingolipids (sphingolipids) are components of cell membranes throughout the body. They break down to ceramide. The major sphingolipidoses (another form of storage disease) include:
Tay-Sachs disease: lack of hexosaminidase A, leading to severe CNS damage in infancy, seizures, eye problems with "cherry
red macula" and muscle weakness. Death in early childhood occurs.
Gaucher's disease: lack of glucocerebrosidase, leading to potential liver, spleen, marrow, and CNS damage. Most cases are mild, with enlarged liver and spleen and bone problems from mass lesions of the macrophages filled with the storage product (glucocerebrosides).
Niemann-Pick disease: lack of sphingomyelinase leads to a storage disease affecting liver, spleen, and CNS, with hepatomegaly, splenomegaly, and severe mental retardation with death in childhood.
Fabry's disease: lack of beta-galactosidase leads to kidney and heart failure in childhood (X-linked). Rare, but popular board question.
Leukodystrophies: rare diseases such as metachromatic leukodystrophy and Krabbe's disease result from lack of enzymes (arylsulfatase and beta-galactosidase respectively) that break down ceramide. The white matter in the brain is mainly affected to produce progressive mental retardation in children and young adults.
Proteins
When there is more protein in the diet than is needed for anabolic (building up tissues such as muscle) functions, then you are in positive nitrogen balance. Lack of dietary protein leads to negative nitrogen balance with catabolism of body tissues, seen in persons with starvation (especially with lack of dietary protein with the disease kwashiorkor, and with type I diabetes).
Transaminases that shuttle amino groups to glutamate are mainly present in the liver. They are elevated in the bloodstream with liver disease.
Excess nitrogen must be elminated by the urea cycle.
Most excess nitrogen eventually appears as ammonia from breakdown of amino acids, purines, pyrimidines, and from growth of bacterial flora.
Part of this cycle occurs within the mitochrondria, where ornithine is converted to citrulline by carbamoyl phosphate, which incorporates free ammonia.
The citrulline is converted to arginine in the cytoplasm by adding another nitrogen with the amino group of aspartate. Arginine splits to urea and ornithine. The urea is excreted by the kidney.
The urea cycle takes place in liver. Liver disease leads to elevations in blood ammonia. The kidneys are able to excrete some excess ammonia by splitting it off glutamine by the action of glutaminase.
There are rare inherited disorders of the urea cycle enzymes. The most common of these is ornithine transcarbamylase (OTC) deficiency, manifested by liver failure and hyperammonemia with death in childhood.
Catabolism of amino acids can take several pathways, and there are several disorders that can occur:
Phenylketonurina (PKU): deficiency of phenylalanine hydroxylase converting phenylalanine to tyrosine, leads to CNS damage with mental retardation. Tested for at birth, because diet in childhood without phenylalanine can prevent damage. Nowadays, people survive with this disease, and women can become pregnant, and they must go back on the diet to prevent hyperphenylalaninemia that can damage the fetus in utero.
Alcaptonuria: deficiency of homogentisic acid oxidase, leads to urine that turns dark on standing with oxidation.
Homocystinuria: deficiency of cystathionine synthetase, leads to mental retardation and decreased bone mass (osteoporosis) and some features such as aortic dissection and dislocated lenses similar to Marfan's syndrome.
Maple syrup urine disease: deficiency of one of several enzymes in the pathway of production of valine, leucine, and isoleucine. Leads to increase in these branched chain amino acids in serum with sweet smelling urine with neurologic damage and death in childhood.
Vitamins
Vitamins are cofactors for a variety of metabolic pathways.
Vitamins are either fat soluble (A, D, E, and K) or water soluble (B and C)
Some D (sunlight exposure) and K (gut bacteria) can be made endogenously
Some storage of fat soluble vitamins takes place, so there is a buffer against deficiency states. A constant dietary supply of B and C is needed.
Thiamine (B1): deficiency causes beri-beri, with heart failure and with peripheral neuropathy. Alcoholics with B1 deficiency may get Wernicke's disease with memory and movement disorders. Pyruvate dehydrogenase requires B1, so lack of B1 increases pyruvate.
Riboflavin (B2): pure deficiency is rare; deficiency leads to cheilosis (cracking of corners of mouth), dermatitis, and tongue abnormalities.
Niacin (B3): deficiency leads to pellagra with diarrhea, dermatitis (in sun-exposed skin) and dementia.
Pyridoxine (B6): deficiency leads to neuropathy. Persons taking the antitubercular drug isoniazid may become B6 deficient.
Biotin: deficiency does not occur
Folic acid: deficiency leads to anemia with large RBCs (macrocytic anemia). Pregnant women with not enough folate have an increased risk for fetuses with neural tube defects.
Cobalamin (B12): deficiency leads to pernicious anemia with large RBCs (macrocytic anemia) and to subacute combined degeneration of the spinal cord with neuropathy
Ascorbic acid (C): deficiency leads to scurvy with capillary fragility and easy bruising, bleeding, anemia, joint pain, and bone pain (and deformity in children).
Retinol (A): deficiency leads to poor function of epithelia (hyperkeratosis, infections), acne, corneal degeneration and scarring (keratomalacia), and night blindness.
Calciferol (D): deficiency in children leads to rickets with bone deformities (can't properly ossify the bone osteoid matrix); in adults the disease osteomalacia resembles osteoporosis (osteoporosis is NOT due to vitamin D or calcium problems).
Alpha-tocopherol (E): deficiency is rare and can lead to anemia and to neurologic problems.
Vitamin K: deficiency leads to bleeding problems because key coagulation factors are not made in the liver when vitamin K is deficient.
Nucleic Acids
Purines are derived from ribose-5-phosphate from the HMP pathway to which are added components of aspartate, glycine, glutamine, and tetrahydrofolate.
Sulfonamide drugs are antimicrobials that competitively inhibit folate synthesis from PABA in micro-organisms (humans are not affected because we do not synthesize folate.
Methotrexate is a chemotherapy agent in humans that competitively inhibits dihydrofolate reductase to slow purine synthesis.
There are no human enzymes to cleave a purine rings, so there is no salvage of them, so the catabolism of purines leads to formation of uric acid.
The last step in the process, conversion of xanthine to uric acid with the enzyme xanthine oxidase, is inhibited by the drug allopurinol, which is used to treat gout, which may be due to excess uric acid production.
In an intermediate pathway, coversion of adenosine to inosine by adenosine deaminase may be blocked by a deficiency of the enzyme, and buildup of the toxic metabolites is toxic to lymphocytes, leading to one form of severe combined immunodeficiency (SCID.)
Some purines are salvaged. The rare disorder Lesch-Nyhan syndrome results from a deficiency of hypoxanthine-guanine phosphoribosyltransferase in the salvage patwhay. There is marked elevation in uric acid with mental retardation, movement disorder, and a peculiar self-mutilation behavior.
Pyrimidines are derived from ribose-5-phosphate from the HMP pathway to which is added components of aspartate, CO2, and glutamine. The key step is formation of carbamoyl phosphate. An intermediate is orotic acid, and deficiency of the enzymes to produce UMP leads to orotic aciduria with growth disturbances and macrocytic anemia.
Most pyrimidines are recycled because enzymes are present that can break down the pyrimidine ring to form precursors of acetyl CoA and succinyl CoA that can re-enter metabolic pathways.
Many chemotherapy agents work by interfering with purine and pyrimidine synthesis to (hopefully) preferentially inhibit the more active DNA synthesis in neoplastic cells.
Methotrexate, by limiting the amount of tetrahydrofolate, prevents methylation of dUMP to dTMP and limits DNA synthesis.
Why do nearly all inherited disorders of metabolism involve the catabolic pathways? Because lack of the anabolic pathways is almost uniformly fatal early in utero. It may take longer for the buildup of a precursor of breakdown to affect the body.
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