Demo – Biochemistry

1. Chylomicrons are involved in the transport of dietary triglycerides from intestine to liver.
2. Very low density lipoproteins (VLDL)are involved in the transport of endogenous triglycerides from liver to peripheral tissues.
3. Low density lipoproteins (LDL) are involved in the transport of cholesterol from liver to peripheral tissues. They are sometimes called bad cholesterol. High levels of LDL cholesterol raise your risk for heart disease and stroke
4. High density lipoproteins (HDL) are involved in the transport of cholesterol form peripheral tissues to liver.

DM Vasudevan textbook of biochemistry for medical student 8^th edition

www.researchgate.com

www.cdc.gov

The Renin-Angiotensin-Aldosterone System (RAAS) is a hormone system within the body that is essential for the regulation of blood pressure and fluid balance.
The system is mainly comprised of the three hormones renin, angiotensin II and aldosterone. Primarily it is regulated by the rate of renal blood flow. When there is a fall in ECF volume, renal plasma flow decreases and this would result in the release of renin by the juxtaglomerular granular cells in response to :
1. Reduced sodium delivery to the distal convoluted tubule detected by macula densa cells.(Salt depletion)
2. Reduced perfusion pressure in the kidney detected by baroreceptors in the afferent arteriole. (Decreased blood pressure)
3. Sympathetic stimulation of the JGA via β1 adrenoreceptors.
4. Prostaglandins
The inhibitors of renin release are:
a. Increased blood pressure b. Salt intake c. Prostaglandin inhibitors d. Angiotensin-II.
Renin cleaves angiotensinogen leucine – leucine at 10 and 11 position to convert it to angiotensin I. Angiotensinogen is an alpha-2 globulin, made in liver. Angiotensin I is then converted to Angiotensin II using an enzyme ACE. Angiotensin-converting enzyme (ACE) is a glycoprotein present in the lung.
This conversion occurs mainly in the lungs where ACE is produced by vascular endothelial cells, although ACE is also generated in smaller quantities within the renal endothelium.
Angiotensin II exerts its action by binding to various receptors throughout the body. It binds to one of two G-protein coupled receptors, the AT1 and AT2 receptors. Most actions occur via the AT1 receptor
Angiotensin-II increases blood pressure by causing vasoconstriction of the arterioles. It stimulates aldosterone production by enhancing conversion of corticosterone to aldosterone. It also inhibits renin release from the juxtaglomerular cells.
Clinical significance
ACE-inhibitors are useful in treating edema and chronic congestive cardiac failure. Various peptide analogs of Angiotensin-II (Saralasin) and antagonists of the converting enzyme (Captopril) are useful to treat renindependent hypertension. Angiotensin-I is inactive; II and III are active.
DM Vasudevan textbook of biochemistry for medical students 8th edition
www.teachmephysiology.com

Niacin is pyridine-3-carboxylic acid. Niacinamide is the acid amide. In NAD+ or NADP+ , the reactive site is the carbon atom 4 and the nitrogen atom of the nicotinamide ring. The co-enzyme is bound to the apo-enzyme.

Co-enzyme Forms of Niacin

Niacin is converted to its co-enzyme forms, viz, Nicotinamide adenine dinucleotide (NAD+ ) and Nicotinamide adenine dinucleotide phosphate (NADP+ ). The niacin is attached to a ribose phosphate to form a mononucleo[1]tide. It is then attached to AMP, to form the dinucleotide. The nitrogen atom of niacinamide contains one positive charge. The structure is abbreviated as NAD+ . (The +ve sign is always shown). In the case of NADP+, one more phosphoric acid is attached to the ribose of the AMP.

One Hydrogen Atom and One Electron

In the oxidized form, nitrogen of the nicotinamide residue has a positive charge. Hence the oxidized form of co-enzyme is usually written as NAD+. In the process of reduction, NAD+ accepts one hydrogen atom fully. The other hydrogen is ionized. Only the electron is accepted. See the positive sign in the molecule is removed.

2H --------------->H + H⁺ + e^-.

Thus NAD+ accepts one H atom and one e- (electron), to form NADH. The hydrogen ion (H+ ) is released

into the surrounding medium. During the oxidation of NADH, the reaction is reversed.

NAD+ Dependent Enzymes

They are so many, that an exhaustive listing is not attempted. One NADH molecule is oxidized in the respiratory chain to generate 2 ½ ATPs. But NADPH is used almost exclusively for reductive biosynthetic reactions.

• Lactate dehydrogenase (lactate → pyruvate)
• Glyceraldehyde-3-phosphate dehydrogenase (glyceraldehyde-3-phosphate → 1,3-bisphosphoglycerate)
• Pyruvate dehydrogenase (pyruvate → acetyl CoA)
• Alpha ketoglutarate dehydrogenase (alpha ketoglutarate → succinyl CoA)
• Beta hydroxyacyl CoA dehydrogenase (beta hydroxyacyl CoA → beta ketoacyl CoA
• Glutamate dehydrogenase (Glutamate → alpha ketoglutarate

NADPH Dependent Reactions

The NADPH generating reactions are shown in Box 37.4. A few examples of NADPH utilizing enzymes are

• Glucose-6-phosphate dehydrogenase in the hexose monophosphate shunt pathway (Glucose-6-phosphate → 6-phospho-glucono lactone)
• 6-phospho gluconate dehydrogenase in the shunt pathway (6-phospho gluconate → 3-keto-6-phospho gluconate).
• Cytoplasmic isocitrate dehydrogenase
• Malic enzyme (malate to pyruvate).

Some enzymes can use either NAD+ or NADP+ as co-enzyme, e.g. glutamate dehydrogenase. In addition to this co-enzyme role, NAD+ is the source of ADP-ribose for the ADP-ribosylation of proteins and poly-ADP-ribosylation of nucleoproteins.

Niacin deficiency

Pellagra

Deficiency of niacin leads to the clinical condition called pellagra. Pellagra is an Italian word, meaning “rough skin”. Pellagra is caused by the deficiency of Tryptophan as well as Niacin. Pellagra is seen more in women; this may be because tryptophan metabolism is inhibited by estrogen metabolites. The symptoms of pellagra are:

• Dermatitis: In early stages, bright red erythema occurs, especially in the feet, ankles and face. Increased pigmentation around the neck is known as Casal’s necklace. The dermatitis is precipitated by exposure to sunlight.
• Diarrhea: The diarrhea may be mild or severe with blood and mucus. This may lead to weight loss. Nausea and vomiting may also be present.
• Dementia: It is frequently seen in chronic cases. Delerium is common in acute pellagra. Irritability, inability to concentrate and poor memory are more common in mild cases. Ataxia, and spasticity are also seen.

Niacin is Synthesized from Tryptophan

Quinolinate phosphoribosyl transferase is the rate limiting enzyme in the conversion of niacin to NAD+ . About 60 mg of tryptophan is equivalent to 1 mg of niacin.

Causes for Niacin Deficiency

• Dietary deficiency of tryptophan: Pellagra is seen among people whose staple diet is maize (South and Central America). In maize, niacin is present; but it is in a bound form, and is unavailable. Pellagra is also seen when staple diet is sorghum (jowar or guinea corn) as in Central and Western India. Sorghum, contains leucine in high quantities. Leucine inhibits the QPRT enzyme, and so niacin cannot be converted to NAD+ (Leucine pellagra).
• Deficient synthesis: Kynureninase, an important enzyme in the pathway of tryptophan, is pyridoxal phosphate dependent. So conversion of tryptophan to niacin is not possible in pyridoxal deficiency.
• Isoniazid (INH): It is an antituberculous drug, which inhibits pyridoxal phosphate formation. Hence, there is block in conversion of tryptophan to NAD+.
• Hartnup disease: Tryptophan absorption from intestine is defective in this congenital disease. Moreover, tryptophan is excreted in urine in large quantities. This leads to lack of tryptophan and consequently deficiency of nicotinamide.
• Carcinoid syndrome: The tumor utilizes major portion of available tryptophan for synthesis of serotonin; so tryptophan is unavailable.

Dietary Sources of Niacin

The richest natural sources of niacin are dried yeast, rice polishing, liver, peanut, whole cereals, legumes, meat and fish. About half of the requirement is met by the conversion of tryptophan to niacin. About 60 mg of tryptophan will yield 1 mg of niacin.

Recommended Daily Allowance (RDA)

Normal requirement is 20 mg/day. During lactation, additional 5 mg is required.

Therapeutic Use of Niacin

Nicotinic acid inhibits the flux of free fatty acids from adipose tissue; so acetyl CoA pool is reduced; and hence serum cholesterol is lowered. In high doses niacin is useful to reduce Lp(a) levels.

Toxicity of Niacin

Nicotinic acid when given orally or parenterally produces a transient vasodilatation of the cutaneous vessels and histamine release. The reaction is accompanied by itching, burning and tingling. Intake of nicotinic acid in excess of 50 mg/day may lead to liver damage.

DM Vasudevan textbook of biochemistry for medical students 7^th edition

Ovarian Hormones

They are C18 estrogens, C19 androgens and C21 progesterone. These are produced by the ovarian follicles. The follicular thecal cells produce C19 androgens. These are converted to C18 estrogens by granulosa cells, by aromatization of ring A and loss of C19 methyl group. Estradiol is the most important estrogen. It is converted to estrone by liver. It is further hydroxylated to estriol, which is inactive.

Estradiol is bound to plasma SHBG (sex hormone binding globulin). Estradiol (E2) is the predominant sex hormone present in females; however, it is present in males, at lower levels, as well. Estradiol has not only a critical impact on reproductive and sexual functioning, but also affects other organs including the bones. Estradiol enters cells freely and interacts with a cytoplasmic target cell receptor; then, estradiol enters the nucleus of the target cell, and regulates gene transcription. Estradiol binds with equal affinity to both estrogen receptors, ER-alpha, and ER-beta. Selective estrogen receptor modulators (SERMs) preferentially act on one of these receptors.

Regulation of Ovarian Hormones

FSH influences follicles to ripen, which produces estrogen. Estrogen level gradually increases in the second week of the menstrual cycle. Estrogen level is maximum 24 hours before the LH peak. High doses of estrogen can suppress the LH release and, therefore effective as contraceptive.

Under the influence of estrogen, uterine endometrium proliferates, glands in endometrium are hypertrophied, ducts in mammary gland are proliferated and progesterone receptors are synthesized. LH level peaks 16 hours before the ovulation. The surge of LH induces the ovulation. The corpus luteum then starts secreting progesterone.

Under the influence of progesterone, endometrium enters the secretory phase, and prepares for implantation of the fertilized ovum. LH is required for maintenance of corpus luteum. If implantation occurs (day 22–24), the LH function is taken over by the hCG, produced by the cytotrophoblast cells of the early embryo. The hCG can be detected 5–7 days after missing a period.

If implantation has not occurred, hormone levels are decreased and the secretory glands of the endometrium are denuded. Clomiphene citrate competes with estrogen for receptors in hypothalamus, thus removing the feedback inhibition. So GnRH level is increased, with consequent high levels of LH and FSH, which may produce follicular stimulation and ovulation. Clomiphene is therefore used to produce ovulation in infertile females.

Certain breast cancers, especially in perimenopausal women are estrogen-dependent. In such patients, estrogen receptor antagonists (Tamoxifen) will block the estrogen receptors, and cancer cells tend to die.

Estradiol

Female (Midcycle)                                          10–50 ng/dL

(1- 10 days of menstrual cycle)                      24–68 pg/ml

(11- 20 days of menstrual cycle)                    50–300 pg/ml

(21- 30 days of menstrual cycle)                    73-149 pg/ml

Male:                                                               < 5 ng/dL

DM Vasudevan textbook of biochemistry for medical students 7^th edition.