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Lecture notes Biomedical Sciences (BSc) BB3703 Medical Biochemistry
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Lecture Notes BB3703 Medical Biochemistry at Brunel University
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BB3703 Medical BiochemistryStructure of Steroid Hormones
Signal transduction pathways
- Signal transduction pathways are pathways of molecular interactions that provide
communication between the cell membrane and intracellular endpoints, leading to come
change in the cell
Hormones
- Hormones are organic chemical messengers produced and secreted by endocrine cells into
the bloodstream. Hormones regulate, integrate and control a wide range of physiologic
functions.
- Hormones transport signals from one cell to another
- There are four major chemical classes or hormones
o Steroid hormones – i.e. progesterone
o Peptide hormones – i.e. insulin
o Amino acid derivatives – epinephrine (adrenaline)
o Prostaglandins and related compounds
- There are three major functional types of hormones
o Endocrine action (e.g. steroid hormones):
The hormone is distributed in blood and binds to distant target cells
o Paracrine action (e.g. prostaglandins):
The hormone acts locally by diffusing from its source to target cells in the
neighbourhood
o Autocrine action (e.g. interleukin-2):
The hormone acts on the same cell that produced it
- A hormone can do all three actions simultaneously, e.g. Corticotrophin Releasing Hormone
(CRH)
- Hormones are required in very small quantities
- Hormones are degraded very rapidly, for this reason they have binding proteins to enable
them to degrade and mask their bioactivity while in the blood stream
- Modern analytical techniques and chemical synthesis are very important
o A patient has come with symptoms due to an endocrinology disorder (either too
high or too low). This is detected by blood tests to check the level of the particular
hormone. Analytical techniques must be sensitive, accurate and specific to
minuscule levels of hormones.
Steroid hormones
- Steroids are lipophilic, low-molecular weight compounds
- Steroid are derived from cholesterol in the smooth endoplasmic reticulum and mitochondria
of endocrine cells.
- Cholesterol is the precursor molecule for all steroid hormones
- Steroid hormones are produced mainly by endocrine glands such as: gonads (testes and
ovaries) and adrenals and during pregnancy by the feto-placental unit.
- Steroids coordinate physiological and behavioural responses for specific biological processes
- Steroids are non-polar (no net charge), and can therefore diffuse across lipid membranes,
such as the plasma membrane. They leave cells shortly after synthesis.
, - Structure of steroids:
o Most steroid have a ‘main’ sterane structure. The sterane system is not broken
down and remains stable.
-
- The conversion of active to inactive forms involves alteration of ring substituents rather than
the ring structure itself.
- The regulation of steroidogenesis involves control of the enzymes which modify cholesterol
into the steroid hormone of interest
- Structure of Cholesterol:
Structure of major steroid hormones in humans
- Pregnenolone
o Produced directly from cholesterol
- Progesterone:
o A progestin produced directly from pregnenolone and secreted from the corpus
luteum
o Responsible for changes associated with luteral phase of the menstrual cycle
o Differentiation factor for mammary glands
- Aldosterone:
o The principal mineralocorticoid produced from progesterone in the zona
glomerulosa of the adrenal cortex
o Raises blood pressure and fluid volume
o Increase Na+ uptake
- Testosterone:
o An androgen produced from progesterone
o Male sex hormone synthesised in the testes
o Responsible for secondary male sex characteristics
- Estradiol:
o An oestrogen produced in the ovary
o Female sex hormone
o Responsible for secondary female sex characteristics
, - Cortisol:
o Dominant glucocorticoid in humans
o Synthesised from progesterone in the zona fasciculata of the adrenal cortex
o Involved in stress adaptation
o Elevates blood pressure and Na+ uptake
o Numerous effects on the immune system
-
- N `Important in all steroidal compounds is their stereochemistry or 3D configuration.
- Stereoisomerism is important for biological activity (i.e. for steroid-protein interactions)
Synthesis of cholesterol
- The main production sites of cholesterol are the liver, skin and intestinal mucosa
- HMG-CoA reductase is activated by insulin and inhibited by glucagon. Phosphorylation
inactivates the enzyme and dephosphorylation activates it. Cholesterol or a cholesterol
derivative inhibits synthesis and stimulates proteolysis of the enzyme
Metabolism of cholesterol
- Cholesterol can become bile acid through the liver or it can act as a hormone in various
tissues.
, Biosynthesis of Steroid Hormones
Adrenal gland diseases
- Hyperfunction (too much) of adrenal cortex
o Cortisol excess (Cushing’s syndrome)
o Androgen excess
o Hyperaldosteronism
- Hypofunction (not enough) of adrenal cortex
o Addison’s disease
o Acute adrenocortical insufficiency
- Congenital adrenal hyperplasia
Steroidogenic Acute Regulatory protein (StAR)
- StAR is a 37-kDa protein. It is identified in almost all steroidogenic tissues and is induced by
trophic hormones
- StAR is the key protein that transports the cholesterol from outside of the cell to the inside
o 37 kDa StAR precursor attaches to a receptor in the mitochondria
o P450 cleave off the cholesterol side chain
o C-terminus of StAR functions in cholesterol transport and the N-terminus begins
import
o Cholesterol is converted to pregnenolone or progesterone which leave the
mitochondria
o Matrix processing proteases yield the 30 kDa protein
o The refolded 30 kDa StAR is degraded
- It is responsible for cholesterol transport in mitochondria. It is the delivery of cholesterol to
the site of first enzymatic conversion that constitutes the rate-limiting and hormonal
regulated step in steroidogenesis. A mutation in this mechanism gives rise to congenital
lipoid adrenal hyperplasia. This gives rise to hyperpigmentation, excess testosterone
synthesis and so forth
- The active form has a rapid turnover
- Cytochrome P450 catalyse the hydroxylation and cleavage of steroid hormones
o CYP11A, CYP11B1 and CYP11B2 are associated with mitochondrial membranes
o CYP17, CYP19 and CYP21 are associated with the endoplasmic reticulum
See lecture handout to check the enzymatic activity of each cytochrome protein
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