NEET MDS Lessons
Biochemistry
Acyl-CoA Synthases (Thiokinases), associated with endoplasmic reticulum membranes and the outer mitochondrial membrane, catalyze activation of long chain fatty acids, esterifying them to coenzyme A, as shown at right. This process is ATP-dependent, and occurs in 2 steps. There are different Acyl-CoA Synthases for fatty acids of different chain lengths.
Exergonic hydrolysis of PPi (P~P), catalyzed by Pyrophosphatase, makes the coupled reaction spontaneous. Overall, two ~P bonds of ATP are cleaved during fatty acid activation. The acyl-coenzyme A product includes one "high energy" thioester linkage.
Summary of fatty acid activation:
- fatty acid + ATP → acyl-adenylate + PPi
PPi → Pi - acyladenylate + HS-CoA → acyl-CoA + AMP
Overall: fatty acid + ATP + HS-CoA → acyl-CoA + AMP + 2 Pi
For most steps of the b-Oxidation Pathway, there are multiple enzymes specific for particular fatty acid chain lengths.
Fatty acid b-oxidation is considered to occur in the mitochondrial matrix. Fatty acids must enter the matrix to be oxidized. However enzymes of the pathway specific for very long chain fatty acids are associated with the inner mitochondrial membrane (facing the matrix).
Fatty acyl-CoA formed outside the mitochondria can pass through the outer mitochondrial membrane, which contains large VDAC channels, but cannot penetrate the mitochondrial inner membrane.
Transfer of the fatty acid moiety across the inner mitochondrial membrane involves carnitine.
Carnitine Palmitoyl Transferases catalyze transfer of a fatty acid between the thiol of Coenzyme A and the hydroxyl on carnitine.
Carnitine-mediated transfer of the fatty acyl moiety into the mitochondrial matrix is a 3-step process, as presented below.
- Carnitine Palmitoyl Transferase I, an enzyme associated with the cytosolic surface of the outer mitochondrial membrane, catalyzes transfer of a fatty acid from ester linkage with the thiol of coenzyme A to the hydroxyl on carnitine.
- Carnitine Acyltransferase, an antiporter in the inner mitochondrial membrane, mediates transmembrane exchange of fatty acyl-carnitine for carnitine.
- Within the mitochondrial matrix (or associated with the matrix surface of the inner mitochondrial membrane, Carnitine Palmitoyl Transferase II catalyzes transfer of the fatty acid from carnitine to coenzyme A. (Carnitine exits the matrix in step 2.) The fatty acid is now esterified to coenzyme A within the mitochondrial matrix
Control of fatty acid oxidation is exerted mainly at the step of fatty acid entry into mitochondria.
Malonyl-CoA inhibits Carnitine Palmitoyl Transferase I. (Malonyl-CoA is also a precursor for fatty acid synthesis). Malonyl-CoA is produced from acetyl-CoA by the enzyme Acetyl-CoA Carboxylase
AMP-Activated Kinase, a sensor of cellular energy levels, catalyzes phosphorylation of Acetyl-CoA Carboxylase under conditions of high AMP (when ATP is low). Phosphorylation inhibits Acetyl-CoA Carboxylase, thereby decreasing malonyl-CoA production.
The decrease in malonyl-CoA concentration releases Carnitine Palmitoyl Transferase I from inhibition. The resulting increase in fatty acid oxidation generates acetyl-CoA for entry into Krebs cycle, with associated production of ATP
ESSENTIAL FATTY ACIDS (EFAs) Polyunsaturated FAs,such as Linoleic acid and g(gamma)- Linolenic acid, are ESSENTIAL FATTY ACIDS — we cannot make them, and we need them, so we must get them in our diets mostly from plant sources.
CHOLESTEROL AND ITS IMPORTANCE
Cholesterol is an important lipid found in the cell membrane. It is a sterol, which means that cholesterol is a combination of a steroid and an alcohol .
It is an important component of cell membranes and is also the basis for the synthesis of other steroids, including the sex hormones estradiol and testosterone, as well as other steroids such as cortisone and vitamin D.
In the cell membrane, the steroid ring structure of cholesterol provides a rigid hydrophobic structure that helps boost the rigidity of the cell membrane.
Without cholesterol the cell membrane would be too fluid. In the human body, cholesterol is synthesized in the liver.
Cholesterol is insoluble in the blood, so when it is released into the blood stream it forms complexes with lipoproteins.
Cholesterol can bind to two types of lipoprotein, called high-density lipoprotein (HDL) and low-density lipoprotein (LDL).
A lipoprotein is a spherical molecule with water soluble proteins on the exterior. Therefore, when cholesterol is bound to a lipoprotein, it becomes blood soluble and can be transported throughout the body.
HDL cholesterol is transported back to the liver. If HDL levels are low, then the blood level of cholesterol will increase.
High levels of blood cholesterol are associated with plaque formation in the arteries, which can lead to heart disease and stroke.
FLUORIDE
The safe limit of fluorine is about 1PPM in water. But excess of fluoride causes Flourosis
Flourosis is more dangerous than caries. When Fluoride content is more than 2 PPM, it will cause chronic intestinal upset, gastroenteritis, loss of weight, osteosclerosis, stratification and discoloration of teeth
Glucagon
Glucagon, a peptide hormone synthesized and secreted from the α-cells of the islets of Langerhans of pancreas, raises blood glucose levels. The pancreas releases glucagon when blood sugar (glucose) levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is released into the bloodstream. Glucagon and insulin are part of a feedback system that keeps blood glucose levels at a stable level.
Regulation and function
Secretion of glucagon is stimulated by hypoglycemia, epinephrine, arginine, alanine, acetylcholine, and cholecystokinin.
Secretion of glucagon is inhibited by somatostatin, insulin, increased free fatty acids and keto acids into the blood, and increased urea production.
Pantothenic Acid
Pantothenic Acid is involved in energy production, and aids in the formation of hormones and the metabolism of fats, proteins, and carbohydrates from food.
RDA The Adequate Intake (AI) for Pantothenic Acid is 5 mg/day for both adult males and females.
Pantothenic Acid Deficiency
Pantothenic Acid deficiency is uncommon due to its wide availability in most foods.
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b Oxidation Pathway |
Fatty Acid Synthesis |
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pathway location |
mitochondrial matrix |
cytosol |
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acyl carriers (thiols) |
Coenzyme-A |
phosphopantetheine (ACP) & cysteine |
|
electron acceptors/donor |
FAD & NAD+ |
NADPH |
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hydroxyl intermediate |
L |
D |
|
2-C product/donor |
acetyl-CoA |
malonyl-CoA (& acetyl-CoA) |