Growth hormone

Growth hormone (GH or HGH), also known as somatotropin or somatropin, is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans.

Growth hormone is a single-chain polypeptide that is synthesized, stored, and secreted by somatotropic cells within the lateral wings of the anterior pituitary gland.

Regulation of growth hormone secretion

Secretion of growth hormone (GH) in the pituitary is regulated by the neurosecretory nuclei of the hypothalamus. These cells release the peptides Growth hormone-releasing hormone (GHRH or somatocrinin) and Growth hormone-inhibiting hormone (GHIH or somatostatin) into the hypophyseal portal venous blood surrounding the pituitary.

GH release in the pituitary is primarily determined by the balance of these two peptides, which in turn is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g., free fatty acids) of GH secretion.

Regulation

Stimulators of growth hormone (GH) secretion include peptide hormones, ghrelin, sex hormones, hypoglycemia, deep sleep, niacin, fasting, and vigorous exercise.

Inhibitors of GH secretion include somatostatin, circulating concentrations of GH and IGF-1 (negative feedback on the pituitary and hypothalamus), hyperglycemia, glucocorticoids, and dihydrotestosterone.

Clinical significance

The most common disease of GH excess is a pituitary tumor composed of somatotroph cells of the anterior pituitary. These somatotroph adenomas are benign and grow slowly, gradually producing more and more GH excess. The adenoma may become large enough to cause headaches, impair vision by pressure on the optic nerves, or cause deficiency of other pituitary hormones by displacement.

CLINICAL SIGNIFICANCE OF ENZYMES

The measurement of enzymes level in serum is applied in diagnostic application

Pancreatic Enzymes

Acute pancreatitis is an inflammatory process where auto digestion of gland was noticed with activation of the certain pancreatic enzymes. Enzymes which involves in pancreatic destruction includes α-amylase, lipase etc.,

1.  α-amylase (AMYs) are calcium dependent hydrolyase class  of metaloenzyme that catalyzes the hydrolysis of 1, 4- α-glycosidic linkages in polysaccharides. The normal values of amylase is in range of 28-100 U/L. Marked increase of 5 to 10 times the upper reference limit (URL) in AMYs activity indicates acute pancreatitis and severe glomerular impairment.

2.  Lipase is single chain glycoprotein. Bile salts and a cofactor called colipase are required for full catalytic activity of lipase. Colipase is secreted by pancreas. Increase in plasma lipase activity indicates acute pancreatitis and carcinoma of the pancreas.

Liver Enzymes

Markers of Hepatocellular Damage

1.  Aspartate transaminase (AST) Aspartate transaminase is present in high concentrations in cells of cardiac and skeletal muscle, liver, kidney and erythrocytes. Damage to any of these tissues may increase plasma AST levels.

The normal value of AST for male is <35 U/ L and for female it is <31 U/L.

2.  Alanine transaminase (ALT) Alanine transaminase is present at high concentrations in liver and to a lesser extent, in skeletal muscle, kidney and heart. Thus in case of liver damage increase in both AST and ALT were noticed. While in myocardial infarction AST is increased with little or no increase in ALT.

The normal value of ALT is <45 U/L and <34 U/L for male and female respectively

Markers of cholestasis

1.  Alkaline phosphatases

Alkaline phosphatases are a group of enzymes that hydrolyse organic phosphates at high pH. They are present in osteoblasts of bone, the cells of the hepatobiliary tract, intestinal wall, renal tubules and placenta.

Gamma-glutamyl-transferase (GGT) Gamma-glutamyl-transferase catalyzes the transfere of the γ–glutamyl group from peptides. The activity of GGT is higher in men than in women. In male the normal value of GGT activity is <55 U/L and for female it is <38 U/L.

2.  Glutamate dehydrogenase (GLD) Glutamate dehydrogenase is a mitochondrial enzyme found in liver, heart muscle and kidneys.

Muscle Enzymes

1.  Creatine Kinase Creatine kinase (CK) is most abundant in cells of brain, cardiac and skeletal.

2.  Lactate Dehydrogenase

Lactate dehydrogenase (LD) catalyses the reversible interconversion of lactate and pyruvate.

PHOSPHORUS

Serum level of phosphate is 3-4 mg/dl for adults and 5-6 mg/dl in children. Consumption of calcitriol increases phosphate absorption.

Functions of phosphorus
(a) Plays key role in formation of tooth and bone

(b) Production of high energy phosphate compounds such as ATP, CTP, GTP etc.,

(c) Synthesis of nucleotide co-enzymes such as NAD and NADP

(d) Formation of phosphodiester backbone structure for DNA and RNA synthesis

Hypophosphatemia is the condition which leads to decrease in absorption of phosphorus. it leads to hypercalcamia

Hyperphosphatemia, increase in absorption of phosphate was noticed. Hyperphosphatemia leads to cell lysis, hypocalcemia and thyrotoxicosis.

COENZYMES

 Enzymes may be simple proteins, or complex enzymes.

A complex enzyme contains a non-protein part, called as prosthetic group (co-enzymes).

Coenzymes are heat stable low molecular weight organic compound. The combined form of protein and the co-enzyme are called as holo-enzyme. The heat labile or unstable part of the holo-enzyme is called as apo-enzyme. The apo-enzyme gives necessary three dimensional structures required for the enzymatic chemical reaction.

Co-enzymes are very essential for the biological activities of the enzyme.

Co-enzymes combine loosely with apo-enzyme and are released easily by dialysis. Most of the co-enzymes are derivatives of vitamin B complex

Glycolysis Pathway

The reactions of Glycolysis take place in the cytosol of cells.

Glucose enters the Glycolysis pathway by conversion to glucose-6-phosphate. Initially, there is energy input corresponding to cleavage of two ~P bonds of ATP. 

1. Hexokinase catalyzes:  glucose + ATP → glucose-6-phosphate + ADP

ATP binds to the enzyme as a complex with Mg⁺⁺.

The reaction catalyzed by Hexokinase is highly spontaneous 

2. Phosphoglucose Isomerase catalyzes: 

glucose-6-phosphate (aldose) → fructose-6-phosphate (ketose)

The Phosphoglucose Isomerase mechanism involves acid/base catalysis, with ring opening, isomerization via an enediolate intermediate, and then ring closure .

3. Phosphofructokinase catalyzes: 

fructose-6-phosphate + ATP  → fructose-1,6-bisphosphate + ADP

The Phosphofructokinase reaction is the rate-limiting step of Glycolysis. The enzyme is highly regulated. 

4. Aldolase catalyzes: 

fructose-1,6-bisphosphate   → dihydroxyacetone phosphate + glyceraldehyde-3-phosphate

The Aldolase reaction is an aldol cleavage, the reverse of an aldol condensation.

5. Triose Phosphate Isomerase (TIM) catalyzes

dihydroxyacetone phosphate (ketose) → glyceraldehyde-3-phosphate (aldose)

Glycolysis continues from glyceraldehydes-3-phosphate

The equilibrium constant (K_eq) for the TIM reaction favors dihydroxyacetone phosphate, but removal of glyceraldehyde-3-phosphate by a subsequent spontaneous reaction allows throughput. 

6. Glyceraldehyde-3-phosphate Dehydrogenase catalyzes:

glyceraldehyde-3-phosphate + NAD⁺ + P_i  → 1,3,bisphosphoglycerate + NADH + H⁺

This is the only step in Glycolysis in which NAD⁺ is reduced to NADH

A cysteine thiol at the active site of Glyceraldehyde-3-phosphate Dehydrogenase has a role in catalysis . 

7. Phosphoglycerate Kinase catalyzes:

1,3-bisphosphoglycerate + ADP  →  3-phosphoglycerate + ATP

This transfer of phosphate to ADP, from the carboxyl group on 1,3-bisphosphoglycerate, is reversible

8. Phosphoglycerate Mutase catalyzes:  3-phosphoglycerate → 2-phosphoglycerate

Phosphate is shifted from the hydroxyl on C3 of 3-phosphoglycerate to the hydroxyl on C2.  

9. Enolase catalyzes:  2-phosphoglycerate  → phosphoenolpyruvate + H₂O

This Mg⁺⁺-dependent dehydration reaction is inhibited by fluoride. Fluorophosphate forms a complex with Mg⁺⁺ at the active site .

10. Pyruvate Kinase catalyzes:  phosphoenolpyruvate + ADP  → pyruvate + ATP

This transfer of phosphate from PEP to ADP is spontaneous. 

Balance sheet for high energy bonds of ATP: 

• 2 ATP expended
• 4 ATP produced (2 from each of two 3C fragments from glucose) 
• Net Production of 2~ P bonds of ATP per glucose