Classification of Fatty Acids and Triglycerides

Short-chain: 2-4 carbon atoms

Medium-chain: 6-12 carbon atoms

Long-chain: 14-20 carbon atoms

Very long-chain: >20 carbon atoms

• are usually in esterified form as major components of other lipids

A16-carbon fatty acid, with one cis double bond between carbon atoms 9 and 10 may be represented as 16:1 cisD⁹.

Double bonds in fatty acids usually have the cis configuration. Most naturally occurring fatty acids have an even number of carbon atoms

Examples of fatty acids

There is free rotation about C-C bonds in the fatty acid hydrocarbon, except where there is a double bond. Each cis double bond causes a kink in the chain,

CLASSIFICATION OF LIPIDS

Lipids are classified as follows:

1. Simple lipids: Esters of fatty acids with various alcohols.

(a) Fats: Esters of fatty acids with glycerol. Oils are fats in the liquid state. A long-chain carboxylic acid; those in animal fats and vegetable oils often have 12–22 carbon atoms.

(b) Waxes: Esters of fatty acids with higher molecular weight monohydric alcohols. Waxes are carboxylic acid esters, RCOOR’ ,with long, straight hydrocarbon chains in both R groups

2. Complex lipids: Esters of fatty acids containing groups in addition to an alcohol and a fatty acid.

(a) Phospholipids: Lipids containing, in addition to fatty acids and an alcohol, a phosphoric acid residue. They frequently have nitrogen containing bases and other substituents,

Eg  glycerophospholipids the alcohol is glycerol

     sphingophospholipids the alcohol is sphingosine.

(b) Glycolipids (glycosphingolipids): Lipids containing a fatty acid, sphingosine, and carbohydrate. These lipids contain a fatty acid, carbohydrate and nitrogenous base. The alcohol  is sphingosine, hence they are also called as glycosphingolipids. Clycerol  and phosphate  are absent  

e.g., cerebrosides, gangliosides.

(c) Other complex lipids: Lipids such as sulfolipids and aminolipids. Lipoproteins may also be placed in this category.

3. Precursor and derived lipids: These include fatty acids, glycerol, steroids, other alcohols, fatty aldehydes, and ketone bodies, hydrocarbons, lipid soluble vitamins, and hormones. Because they are uncharged, acylglycerols (glycerides), cholesterol, and cholesteryl esters are termed neutral lipids

4. Miscellaneous lipids: These include a large number of compounds possessing the characteristics of lipids e.g., carotenoids, squalene, hydrocarbons such as pentacosane (in bees wax), terpenes etc.

NEUTRAL LIPIDS: The lipids which are uncharged are referred to as neutral lipids. These are mono-, di-, and triacylglycerols, cholesterol and cholesteryl esters.

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 PP_i (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 + PP_i
  PP_i  → P_i
• acyladenylate + HS-CoA → acyl-CoA + AMP

Overall: fatty acid + ATP + HS-CoA → acyl-CoA + AMP +  2 P_i

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.

1. 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.
2. Carnitine Acyltransferase, an antiporter in the inner mitochondrial membrane, mediates transmembrane exchange of fatty acyl-carnitine for carnitine.
3. 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

Thyroid Hormones

Thyroid hormones (T4 and T3) are tyrosine-based hormones produced by the follicular cells of the thyroid gland and are regulated by TSH made by the thyrotropes of the anterior pituitary gland, are primarily responsible for regulation of metabolism. Iodine is necessary for the production of T3 (triiodothyronine) and T4 (thyroxine).

A deficiency of iodine leads to decreased production of T3 and T4, enlarges  the thyroid tissue and will cause the disease known as goitre.

Thyroid hormones are transported by Thyroid-Binding Globulin

Thyroxine binding globulin (TBG), a glycoprotein binds T4 and T3 and has the capacity to bind 20 μg/dL of plasma.

Diseases

1. Hyperthyroidism (an example is Graves Disease) is the clinical syndrome caused by an excess of circulating free thyroxine, free triiodothyronine, or both. It is a common disorder that affects approximately 2% of women and 0.2% of men.

2 Hypothyroidism (an example is Hashimoto’s thyroiditis) is the case where there is a deficiency of thyroxine, triiodiothyronine, or both.

Amino Acid Biosynthesis

Glutamate and Aspartate

Glutamate and aspartate are synthesized from their widely distributed a-keto acid precursors by simple 1-step transamination reactions. The former catalyzed by glutamate dehydrogenase and the latter by aspartate aminotransferase, AST. Aspartate is also derived from asparagine through the action of asparaginase. The importance of glutamate as a common intracellular amino donor for transamination reactions and of aspartate as a precursor of ornithine for the urea cycle is described in the Nitrogen Metabolism page.
 

Alanine and the Glucose-Alanine Cycle

Role in protein synthesis,

Alanine is second only to glutamine in prominence as a circulating amino acid.. When alanine transfer from muscle to liver is coupled with glucose transport from liver back to muscle, the process is known as the glucose-alanine cycle. The key feature of the cycle is that in 1 molecule, alanine, peripheral tissue exports pyruvate and ammonia (which are potentially rate-limiting for metabolism) to the liver, where the carbon skeleton is recycled and most nitrogen eliminated.

There are 2 main pathways to production of muscle alanine: directly from protein degradation, and via the transamination of pyruvate by alanine transaminase, ALT (also referred to as serum glutamate-pyruvate transaminase, SGPT).

glutamate + pyruvate <-------> a-KG + alanine

Cysteine Biosynthesis

The sulfur for cysteine synthesis comes from the essential amino acid methionine. A condensation of ATP and methionine catalyzed by methionine adenosyltransferase yields S-adenosylmethionine

Tyrosine Biosynthesis

Tyrosine is produced in cells by hydroxylating the essential amino acid phenylalanine. This relationship is much like that between cysteine and methionine. Half of the phenylalanine required goes into the production of tyrosine; if the diet is rich in tyrosine itself, the requirements for phenylalanine are reduced by about 50%.

Phenylalanine hydroxylase is a mixed-function oxygenase: one atom of oxygen is incorporated into water and the other into the hydroxyl of tyrosine. The reductant is the tetrahydrofolate-related cofactor tetrahydrobiopterin, which is maintained in the reduced state by the NADH-dependent enzyme dihydropteridine reductase (DHPR).

Ornithine and Proline Biosynthesis

Glutamate is the precursor of both proline and ornithine, with glutamate semialdehyde being a branch point intermediate leading to one or the other of these 2 products. While ornithine is not one of the 20 amino acids used in protein synthesis, it plays a significant role as the acceptor of carbamoyl phosphate in the urea cycle

Serine Biosynthesis

The main pathway to serine starts with the glycolytic intermediate 3-phosphoglycerate. An NADH-linked dehydrogenase converts 3-phosphoglycerate into a keto acid, 3-phosphopyruvate, suitable for subsequent transamination. Aminotransferase activity with glutamate as a donor produces 3-phosphoserine, which is converted to serine by phosphoserine phosphatase.
 

Glycine Biosynthesis

The main pathway to glycine is a 1-step reaction catalyzed by serine hydroxymethyltransferase. This reaction involves the transfer of the hydroxymethyl group from serine to the cofactor tetrahydrofolate (THF), producing glycine and N⁵,N¹⁰-methylene-THF. Glycine produced from serine or from the diet can also be oxidized by glycine cleavage complex, GCC, to yield a second equivalent of N⁵,N¹⁰-methylene-tetrahydrofolate as well as ammonia and CO₂.

Glycine is involved in many anabolic reactions other than protein synthesis including the synthesis of purine nucleotides, heme, glutathione, creatine and serine.

Aspartate/Asparagine and Glutamate/Glutamine Biosynthesis

Glutamate is synthesized by the reductive amination of a-ketoglutarate catalyzed by glutamate dehydrogenase; it is thus a nitrogen-fixing reaction. In addition, glutamate arises by aminotransferase reactions, with the amino nitrogen being donated by a number of different amino acids. Thus, glutamate is a general collector of amino nitrogen.

Aspartate is formed in a transamintion reaction catalyzed by aspartate transaminase, AST. This reaction uses the aspartate a-keto acid analog, oxaloacetate, and glutamate as the amino donor. Aspartate can also be formed by deamination of asparagine catalyzed by asparaginase.

Asparagine synthetase and glutamine synthetase, catalyze the production of asparagine and glutamine from their respective a-amino acids. Glutamine is produced from glutamate by the direct incorporation of ammonia; and this can be considered another nitrogen fixing reaction. Asparagine, however, is formed by an amidotransferase reaction.

Aminotransferase reactions are readily reversible. The direction of any individual transamination depends principally on the concentration ratio of reactants and products. By contrast, transamidation reactions, which are dependent on ATP, are considered irreversible. As a consequence, the degradation of asparagine and glutamine take place by a hydrolytic pathway rather than by a reversal of the pathway by which they were formed. As indicated above, asparagine can be degraded to aspartate

The Phosphate Buffer System

This system, which acts in the cytoplasm of all cells, consists of H₂PO₄^–  as proton donor and HPO₄ ^2– as proton acceptor :

H₂PO₄^–  = H⁺ + H₂PO₄^–

The phosphate buffer system works exactly like the acetate buffer system, except for the pH range in which it functions. The phosphate buffer system is maximally effective at a pH close to its pKa of 6.86 and thus tends to resist pH changes in the range between 6.4 and 7.4. It is, therefore, effective in providing buffering power in intracellular fluids.