NEET MDS Lessons
Biochemistry
Amino Acid Catabolism
Glutamine/Glutamate and Asparagine/Aspartate Catabolism
Glutaminase is an important kidney tubule enzyme involved in converting glutamine (from liver and from other tissue) to glutamate and NH3+, with the NH3+ being excreted in the urine. Glutaminase activity is present in many other tissues as well, although its activity is not nearly as prominent as in the kidney. The glutamate produced from glutamine is converted to a-ketoglutarate, making glutamine a glucogenic amino acid.
Asparaginase is also widely distributed within the body, where it converts asparagine into ammonia and aspartate. Aspartate transaminates to oxaloacetate, which follows the gluconeogenic pathway to glucose.
Glutamate and aspartate are important in collecting and eliminating amino nitrogen via glutamine synthetase and the urea cycle, respectively. The catabolic path of the carbon skeletons involves simple 1-step aminotransferase reactions that directly produce net quantities of a TCA cycle intermediate. The glutamate dehydrogenase reaction operating in the direction of a-ketoglutarate production provides a second avenue leading from glutamate to gluconeogenesis.
Alanine Catabolism
Alanine is also important in intertissue nitrogen transport as part of the glucose-alanine cycle. Alanine's catabolic pathway involves a simple aminotransferase reaction that directly produces pyruvate. Generally pyruvate produced by this pathway will result in the formation of oxaloacetate, although when the energy charge of a cell is low the pyruvate will be oxidized to CO2 and H2O via the PDH complex and the TCA cycle. This makes alanine a glucogenic amino acid.
Arginine, Ornithine and Proline Catabolism
The catabolism of arginine begins within the context of the urea cycle. It is hydrolyzed to urea and ornithine by arginase.
Ornithine, in excess of urea cycle needs, is transaminated to form glutamate semialdehyde. Glutamate semialdehyde can serve as the precursor for proline biosynthesis as described above or it can be converted to glutamate.
Proline catabolism is a reversal of its synthesis process.
The glutamate semialdehyde generated from ornithine and proline catabolism is oxidized to glutamate by an ATP-independent glutamate semialdehyde dehydrogenase. The glutamate can then be converted to α-ketoglutarate in a transamination reaction. Thus arginine, ornithine and proline, are glucogenic.
Methionine Catabolism
The principal fates of the essential amino acid methionine are incorporation into polypeptide chains, and use in the production of α -ketobutyrate and cysteine via SAM as described above. The transulfuration reactions that produce cysteine from homocysteine and serine also produce α -ketobutyrate, the latter being converted to succinyl-CoA.
Regulation of the methionine metabolic pathway is based on the availability of methionine and cysteine
Phenylalanine and Tyrosine Catabolism
Phenylalanine normally has only two fates: incorporation into polypeptide chains, and production of tyrosine via the tetrahydrobiopterin-requiring phenylalanine hydroxylase. Thus, phenylalanine catabolism always follows the pathway of tyrosine catabolism. The main pathway for tyrosine degradation involves conversion to fumarate and acetoacetate, allowing phenylalanine and tyrosine to be classified as both glucogenic and ketogenic.
Tyrosine is equally important for protein biosynthesis as well as an intermediate in the biosynthesis of several physiologically important metabolites e.g. dopamine, norepinephrine and epinephrine
Factors regulating blood calcium level
(i) Vitamin D
(a) Vitamin D and absorption of calcium: Active form of calcium is calcitriol. Calcitriol enters intestinal wall and binds to cytoplasmic receptor and then binds with DNA causes depression and consequent transcription of gene code for calbindin. Due to increased availability of calbindin, absorption of calcium increases leading to increased blood calcium level.
(b) Vitamin D and Bone: Vitamin D activates osteoblast, bone forming cells & also stimulates secretion of alkaline phosphatase. Due to this enzyme, calcium and phosphorus increase.
(c) Vitamin D and Kidney: Calcitriol increase reabsorption of calcium and phosphorus by renal tubules.
(ii) Parathyroid hormone (PTH)
Normal PTH level in serum is 10-60ng/l.
(a) PTH and bones: In bone, PTH causes demineralization. It also causes recreation of collagenase from osteoclast leads to loss of matrix and bone resorption. As a result, mucopolysacharides and hydroxyproline are excreted in urine.
(b) PTH and Kidney: In kidney, PTH causes increased reabsorption of calcium but decreases reabsorption of phosphorus from kidney tubules.
(iii) Calcitonin Calcitonin decreases serum calcium level. It inhibits resorption of bone. It decreases the activity of osteoclasts and increases osteoblasts.
Hyper Calcemia When plasma Ca2+ level is more than 11mg/dl is called Hypercalcemia. It is due to parathyroid adenoma or ectopic PTH secreting tumor. calcium excreted in urine decreases excretion of chloride causing hyperchloremic acidosis.
Hypocalcemia Plasma calcium level less than 8mg/dl is called hypocalcemia. Tetany due to accidental surgical removal of parathyroid glands or by autoimmune disease. In tetany, neuromuscular irritability is increased. Increased Q-7 internal in ECG is seen. Main manifestation is carpopedal spasm. Laryngismus and stridor are also observed.
The Protein Buffer Systems
The protein buffers are very important in the plasma and the intracellular fluids but their concentration is very low in cerebrospinal fluid, lymph and interstitial fluids.
The proteins exist as anions serving as conjugate bases (Pr − ) at the blood pH 7.4 and form conjugate acids (HPr) accepting H+ . They have the capacity to buffer some H2CO3 in the blood.
- There are two important phospholipids, Phosphatidylcholine and Phosphatidylserine found the cell membrane without which cell cannot function normally.
- Phospholipids are also important for optimal brain health as they found the cell membrane of brain cells also which help them to communicate and influence the receptors function. That is the reason food stuff which is rich in phospholipids like soy, eggs and the brain tissue of animals are good for healthy and smart brain.
- Phospholipids are the main component of cell membrane or plasma membrane. The bilayer of phospholipid molecules determine the transition of minerals, nutrients, and drugs in and out of the cell and affect various functions of them.
- As phospholipids are main component of all cell membrane, they influence a number of organs and tissues, such as the heart, blood cells and the immune system. As we grown up the amount of phospholipids decreases and reaches to decline.
- Phospholipids present in cell membrane provide cell permeability and flexibility with various substances as well its ability to move fluently. The arrangement of phospholipid molecules in lipid bilayer prevent amino acids, carbohydrates, nucleic acids, and proteins from moving across the membrane by diffusion. The lipid bi-layer is usually help to prevent adjacent molecules from sticking to each other.
- The selectivity of cell membrane form certain substances are due to the presence of hydrophobic and hydrophilic part molecules and their arrangement in bilayer. This bilayer is also maintained the normal pH of cell to keeps it functioning properly.
- Phospholipids are also useful in the treatment of memory problem associated with chronic substances as they improve the ability of organism to adapt the chronic stress.
Step 1. Acyl-CoA Dehydrogenase catalyzes oxidation of the fatty acid moiety of acyl-CoA, to produce a double bond between carbon atoms 2 and 3.
There are different Acyl-CoA Dehydrogenases for short (4-6 C), medium (6-10 C), long and very long (12-18 C) chain fatty acids. Very Long Chain Acyl-CoA Dehydrogenase is bound to the inner mitochondrial membrane. The others are soluble enzymes located in the mitochondrial matrix.
FAD is the prosthetic group that functions as electron acceptor for Acyl-CoA Dehydrogenase.
A glutamate side-chain carboxyl extracts a proton from the a-carbon of the substrate, facilitating transfer of 2 e- with H+ (a hydride) from the b position to FAD. The reduced FAD accepts a second H+, yielding FADH2
The carbonyl oxygen of the thioester substrate is hydrogen bonded to the 2'-OH of the ribityl moiety of FAD, giving this part of FAD a role in positioning the substrate and increasing acidity of the substrate a-proton
The reactive glutamate and FAD are on opposite sides of the substrate at the active site. Thus the reaction is stereospecific, yielding a trans double bond in enoyl-CoA.
FADH2 of Acyl CoA Dehydrogenase is reoxidized by transfer of 2 electrons to an Electron Transfer Flavoprotein (ETF), which in turn passes the electrons to coenzyme Q of the respiratory chain.
Step 2. Enoyl-CoA Hydratase catalyzes stereospecific hydration of the trans double bond produced in the 1st step of the pathway, yielding L-hydroxyacyl-Coenzyme A
Step 3. Hydroxyacyl-CoA Dehydrogenase catalyzes oxidation of the hydroxyl in the b position (C3) to a ketone. NAD+ is the electron acceptor.
Step 4. b-Ketothiolase (b-Ketoacyl-CoA Thiolase) catalyzes thiolytic cleavage.
A cysteine S attacks the b-keto C. Acetyl-CoA is released, leaving the fatty acyl moiety in thioester linkage to the cysteine thiol. The thiol of HSCoA displaces the cysteine thiol, yielding fatty acyl-CoA (2 C shorter).
A membrane-bound trifunctional protein complex with two subunit types expresses the enzyme activities for steps 2-4 of the b-oxidation pathway for long chain fatty acids. Equivalent enzymes for shorter chain fatty acids are soluble proteins of the mitochondrial matrix.
Summary of one round of the b-oxidation pathway:
fatty acyl-CoA + FAD + NAD+ + HS-CoA →
fatty acyl-CoA (2 C shorter) + FADH2 + NADH + H+ + acetyl-CoA
The b-oxidation pathway is cyclic. The product, 2 carbons shorter, is the input to another round of the pathway. If, as is usually the case, the fatty acid contains an even number of C atoms, in the final reaction cycle butyryl-CoA is converted to 2 copies of acetyl-CoA
ATP production:
- FADH2 of Acyl CoA Dehydrogenase is reoxidized by transfer of 2 e- via ETF to coenzyme Q of the respiratory chain. H+ ejection from the mitochondrial matrix that accompanies transfer of 2 e- from CoQ to oxygen, leads via chemiosmotic coupling to production of approximately 1.5 ATP. (Approx. 4 H+ enter the mitochondrial matrix per ATP synthesized.)
- NADH is reoxidized by transfer of 2 e- to the respiratory chain complex I. Transfer of 2 e- from complex I to oxygen yields approximately 2.5 ATP.
- Acetyl-CoA can enter Krebs cycle, where the acetate is oxidized to CO2, yielding additional NADH, FADH2, and ATP.
- Fatty acid oxidation is a major source of cellular ATP
b-Oxidation of very long chain fatty acids also occurs within peroxisomes
FAD is electron acceptor for peroxisomal Acyl-CoA Oxidase, which catalyzes the first oxidative step of the pathway. The resulting FADH2 is reoxidized in the peroxisome producing hydrogen peroxide FADH2 + O2 à FAD + H2O2
The peroxisomal enzyme Catalase degrades H2O2 by the reaction:
2 H2O2 → 2 H2O + O2
These reactions produce no ATP
Once fatty acids are reduced in length within the peroxisomes they may shift to the mitochondria to be catabolized all the way to CO2. Carnitine is also involved in transfer of fatty acids into and out of peroxisomes
IRON
The normal limit for iron consumption is 20 mg/day for adults, 20-30 mg/day for children and 40 mg/day for pregnant women.
Milk is considered as a poor source of iron.
Factors influencing absorption of iron Iron is absorbed by upper part of duodenum and is affected by various factors
(a) Only reduced form of iron (ferrous) is absorbed and ferric form are not absorbed
(b) Ascorbic acid (Vitamin C) increases the absorption of iron (c) The interfering substances such as phytic acid and oxalic acid decreases absorption of iron
Regulation of absorption of Iron
Absorption of iron is regulated by three main mechanisms, which includes
(a) Mucosal Regulation
(b) Storer regulation
(c) Erythropoietic regulation
In mucosal regulation absorption of iron requires DM-1 and ferroportin. Both the proteins are down regulated by hepcidin secreted by liver. The above regulation occurs when the body irons reserves are adequate. When the body iron content gets felled, storer regulation takes place. In storer regulation the mucosal is signaled for increase in iron absorption. The erythropoietic regulation occurs in response to anemia. Here the erythroid cells will signal the mucosa to increase the iron absorption.
Iron transport in blood
The transport form of iron in blood is transferin. Transferin are glycoprotein secreted by liver. In blood, the ceruloplasmin is the ferroxidase which oxidizes ferrous to ferric state.
Storage form of iron is ferritin. Almost no iron is excreted through urine.
Anemia
Anemia is the most common nutritional deficiency disease. The microscopic appearance of anemia is characterized by microcytic hypochromic anemia
The abnormal gene responsible for hemosiderosis is located on the short arm of chromosome No.6.
The main causes of iron deficiency or anemia are
(a) Nutritional deficiency of iron (b) Lack of iron absorption (c) Hook worm infection (d) Repeated pregnancy (e) Chronic blood loss (f) Nephrosis (g) Lead poisoning
Glycogen Storage Diseases are genetic enzyme deficiencies associated with excessive glycogen accumulation within cells.
- When an enzyme defect affects mainly glycogen storage in liver, a common symptom is hypoglycemia (low blood glucose), relating to impaired mobilization of glucose for release to the blood during fasting.
- When the defect is in muscle tissue, weakness and difficulty with exercise result from inability to increase glucose entry into Glycolysis during exercise.
Various type of Glycogen storage disease are
|
Type |
Name |
Enzyme Deficient |
|
I |
Von Geirke’s Disease |
Glucose -6-phosphate |
|
II |
Pompe’s Disease |
(1, 4)glucosidase |
|
III |
Cori’s Disease |
Debranching Enzymes |
|
IV |
Andersen’s Disease |
Branching Enzymes |
|
V |
McArdle’s Disease |
Muscles Glycogen Phosphorylase |