Bilirubin Metabolism

Bilirubin (formerly referred to as hematoidin) is the yellow breakdown product of normal heme catabolism. Heme is formed from hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile, and its levels are elevated in certain diseases. It is responsible for the yellow color of bruises and the yellow discoloration in jaundice.

Function:

Bilirubin is created by the activity of biliverdin reductase on biliverdin. Bilirubin, when oxidized, reverts to become biliverdin once again. This cycle, in addition to the demonstration of the potent antioxidant activity of bilirubin, has led to the hypothesis that bilirubin's main physiologic role is as a cellular antioxidant.

Metabolism

Erythrocytes (red blood cells) generated in the bone marrow are disposed of in the spleen when they get old or damaged. This releases hemoglobin, which is broken down to heme, as the globin parts are turned into amino acids. The heme is then turned into unconjugated bilirubin in the macrophages of the spleen. This unconjugated bilirubin is not soluble in water. It is then bound to albumin and sent to the liver.

In the liver it is conjugated with glucuronic acid, making it soluble in water. Much of it goes into the bile and thus out into the small intestine. Some of the conjugated bilirubin remains in the large intestine and is metabolised by colonic bacteria to urobilinogen, which is further metabolized to stercobilinogen, and finally oxidised to stercobilin. This stercobilin gives feces its brown color. Some of the urobilinogen is reabsorbed and excreted in the urine along with an oxidized form, urobilin.

Normally, a tiny amount of bilirubin is excreted in the urine, accounting for the light yellow color. If the liver’s function is impaired or when biliary drainage is blocked, some of the conjugated bilirubin leaks out of the hepatocytes and appears in the urine, turning it dark amber. The presence of this conjugated bilirubin in the urine can be clinically analyzed, and is reported as an increase in urine bilirubin. However, in disorders involving hemolytic anemia, an increased number of red blood cells are broken down, causing an increase in the amount of unconjugated bilirubin in the blood. As stated above, the unconjugated bilirubin is not water soluble, and thus one will not see an increase in bilirubin in the urine. Because there is no problem with the liver or bile systems, this excess unconjugated bilirubin will go through all of the normal processing mechanisms that occur (e.g., conjugation, excretion in bile, metabolism to urobilinogen, reabsorption) and will show up as an increase in urine urobilinogen. This difference between increased urine bilirubin and increased urine urobilinogen helps to distinguish between various disorders in those systems.

Palmitic Acid

Alpha Helix

Alpha helix (α-helix) is a right- or left-handed coiled conformation, resembling a spring, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier (i+4 \rightarrow i hydrogen bonding). This secondary structure is also sometimes called a classic Pauling-Corey-Branson alpha helix.

Structure

Geometry and hydrogen bonding

The amino acids in an α helix are arranged in a right-handed helical structure where each amino acid corresponds to a 100° turn in the helix (i.e., the helix has 3.6 residues per turn), and a translation of 1.5 Å (= 0.15 nm) along the helical axis. The pitch of the helix (the vertical distance between two points on the helix) is 5.4 Å (= 0.54 nm)which is the product of 1.5 and 3,6. Most importantly, the N-H group of an amino acid forms a hydrogen bond with the C=O group of the amino acid four residues earlier; this repeated i+4 \rightarrow i hydrogen bonding defines an α-helix. Similar structures include the 310 helix (i+3 \rightarrow i hydrogen bonding) and the π-helix (i+5 \rightarrow i hydrogen bonding). These alternative helices are relatively rare, although the 310 helix is often found at the ends of α-helices, "closing" them off. Transient i+2 \rightarrow i helices (sometimes called δ-helices) have also been reported as intermediates in molecular dynamics simulations of α-helical folding.

Residues in α-helices typically adopt backbone (φ, ψ) dihedral angles around (-60°, -45°). More generally, they adopt dihedral angles such that the ψ dihedral angle of one residue and the φ dihedral angle of the next residue sum to roughly -105°. Consequently, α-helical dihedral angles generally fall on a diagonal stripe on the Ramachandran plot (of slope -1), ranging from (-90°, -15°) to (-35°, -70°). For comparison, the sum of the dihedral angles for a 310 helix is roughly -75°, whereas that for the π-helix is roughly -130°. The general formula for the rotation angle Ω per residue of any polypeptide helix with trans isomers is given by the equation.

The α-helix is tightly packed; there is almost no free space within the helix. The amino-acid side chains are on the outside of the helix, and point roughly "downwards" (i.e., towards the N-terminus), like the branches of an evergreen tree (Christmas tree effect). This directionality is sometimes used in preliminary, low-resolution electron-density maps to determine the direction of the protein backbone.

Stability

Helices observed in proteins can range from four to over forty residues long, but a typical helix contains about ten amino acids (about three turns). Short polypeptides generally do not exhibit much alpha helical structure in solution, since the entropic cost associated with the folding of the polypeptide chain is not compensated for by a sufficient amount of stabilizing interactions. The backbone hydrogen bonds of α-helices are generally considered slightly weaker than those found in β-sheets, and are readily attacked by the ambient water molecules. However, in more hydrophobic environments such as the plasma membrane, or in the presence of co-solvents such as trifluoroethanol (TFE), or isolated from solvent in the gas phase,[6] oligopeptides readily adopt stable α-helical structure.

Alanine

Alanine (abbreviated as Ala or A) is an α-amino acid with the chemical formula CH3CH(NH2)COOH. The L-isomer is one of the 20 proteinogenic amino acids, i.e. the building blocks of proteins. Its codons are GCU, GCC, GCA, and GCG. It is classified as a non-polar amino acid. L-alanine is second only to leucine, accounting for 7.8% of the primary structure in a sample of 1,150 proteins. D-alanine occurs in bacterial cell walls and in some peptide antibiotics.

Structure

The α-carbon atom of alanine is bound with a methyl group (-CH3), making it one of the simplest α-amino acids with respect to molecular structure and also resulting in alanine being classified as an aliphatic amino acid. The methyl group of alanine is non-reactive and is thus almost never directly involved in protein function.

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Physiological function

Alanine plays a key role in glucose-alanine cycle between tissues and liver. In muscle and other tissues that degrade amino acids for fuel, amino groups are collected in the form of glutamate by transamination. Glutamate can then transfer its amino group through the action of alanine aminotransferase to pyruvate, a product of muscle glycolysis, forming alanine and alpha-ketoglutarate. The alanine formed is passed into the blood and transported to the liver. A reverse of the alanine aminotransferase reaction takes place in liver. Pyruvate regenerated forms glucose through gluconeogenesis, which returns to muscle through the circulation system. Glutamate in the liver enters mitochondria and degrades into ammonium ion through the action of glutamate dehydrogenase, which in turn participate in the urea cycle to form urea.

Glucose-alanine cycle enables pyruvate and glutamate to be removed from muscle and find their ways to liver. Glucose is able to be regenerated from pyruvate and returned to muscle. The energetic burden of gluconeogenesis is thus imposed on the liver instead of the muscle. All available ATP in muscle is devoted to muscle contraction.