Weak Acids and pKa

• The strength of an acid can be determined by its dissociation constant, Ka.

• Acids that do not dissociate significantly in water are weak acids.

• The dissociation of an acid is expressed by the following reaction: HA = H⁺ + A^- and the dissociation constant Ka = [H⁺ ][A^- ] / [HA]  

• When Ka < 1, [HA] > [H⁺ ][A^- ] and HA is not significantly dissociated. Thus, HA is a weak acid when ka < 1.

• The lesser the value of Ka, the weaker the acid.

• Similar to pH, the value of Ka can also be represented as pKa.

• pKa = -log Ka.

• The larger the pKa, the weaker the acid.

• pKa is a constant for each conjugate acid and its conjugate base pair.

• Most biological compounds are weak acids or weak bases.

Regulation of PTH secretion

Secretion of parathyroid hormone is controlled chiefly by serum [Ca²⁺] through negative feedback. Calcium-sensing receptors located on parathyroid cells are activated when [Ca²⁺] is low.

Hypomagnesemia inhibits PTH secretion and also causes resistance to PTH, leading to a form of hypoparathyroidism that is reversible.

Hypermagnesemia also results in inhibition of PTH secretion.

Stimulators of PTH includes decreased serum [Ca²⁺], mild decreases in serum [Mg²⁺], and an increase in serum phosphate.

Inhibitors include increased serum [Ca²⁺], severe decreases in serum [Mg²⁺], which also produces symptoms of hypoparathyroidism (such as hypocalcemia), and calcitriol.

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

Positively Charged (Basic)

 Mnemonic: "His Lies Are Basic" (Histidine, Lysine, Arginine)

Negatively Charged (Acidic)

Mnemonic: "Acidic Dragons Eat" (D = Aspartate, E = Glutamate)

Pepsin

• Primary enzyme for protein degradation in stomach
• Optimal pH: 1.5-2.0 (acidic)
• Secreted as inactive pepsinogen
• Cleaves proteins into smaller peptides

Histone

• Protein rich in basic amino acids (lysine and arginine)
• Packages DNA in chromosomes
• Forms nucleosomes with DNA
• Types: H1, H2A, H2B, H3, H4

Casein

• Example of phosphoprotein
• Major protein in milk
• Contains phosphate groups attached to serine residues
• Forms micelles in milk

Antibodies (Immunoglobulins)

• Structure composed of 2 long (heavy) & 2 short (light) peptide chains
• Y-shaped structure
• Connected by disulfide bonds
• Variable regions bind to antigens
• Constant regions determine antibody class

Insulin Receptors

• Tetrameric glycoprotein
• Consists of 2 α and 2 β subunits
• α subunits: Extracellular, insulin-binding
• β subunits: Transmembrane, tyrosine kinase activity
• Essential for glucose homeostasis

Collagen

• Contains triple helix structure
• Most abundant protein in mammals
• Composed of three polypeptide chains (tropocollagen)
• Amino acid sequence: Gly-X-Y (where X is often proline, Y is often hydroxyproline)
• Provides structural support to tissues

Nomenclature for stereoisomers: D and L designations are based on the configuration about the single asymmetric carbon in glyceraldehydes

For sugars with more than one chiral center, the D or L designation refers to the asymmetric carbon farthest from the aldehyde or keto group.

Most naturally occurring sugars are D isomers.

D & L sugars are mirror images of one another. They have the same name. For example, D-glucose and L-glucose

Other stereoisomers have unique names, e.g., glucose, mannose, galactose, etc. The number of stereoisomers is 2 ⁿ, where n is the number of asymmetric centers. The six-carbon aldoses have 4 asymmetric centers, and thus 16 stereoisomers (8 D-sugars and 8 L-sugars

An aldehyde can react with an alcohol to form a hemiacetal

Similarly a ketone can react with an alcohol to form a hemiketal

Pentoses and hexoses can cyclize, as the aldehyde or keto group reacts with a hydroxyl on one of the distal carbons

E.g., glucose forms an intra-molecular hemiacetal by reaction of the aldehyde on C1 with the hydroxyl on C5, forming a six-member pyranose ring, named after the compound pyran

The representations of the cyclic sugars below are called Haworth projections.

Fructose can form either: 

• a six-member pyranose ring, by reaction of the C2 keto group with the hydroxyl on C6
• a 5-member furanose ring, by reaction of the C2 keto group with the hydroxyl on C5.

Cyclization of glucose produces a new asymmetric center at C1, with the two stereoisomers called anomers, α & β

Haworth projections represent the cyclic sugars as having essentially planar rings, with the OH at the anomeric C1 extending either:

• below the ring (α)
• above the ring (β).

Because of the tetrahedral nature of carbon bonds, the cyclic form of pyranose sugars actually assume a "chair" or "boat" configuration, depending on the sugar