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Biochemistry Objectives 47
1.
Biochemical origin of:
a.
PTH: synthesized as prepro-PTH in the parathyroid and cleaved similarly
to insulin; synthesized and released in released in response to low Ca2+
b.
Calcitonin: synthesized as prepro-calcitonin in thyroid C cells and
cleaved to make calcitionin
a. Alternative splicing to produce CT and CGRP: the calcitonin gene can
be alternatively spliced to produce prepro-CGRP, the precursor to
CGRP, an extremely potent vasodilator.
c.
1,25(OH)2D3:
vitamin D is produced by UV cleavage of 7dehydrocholesterol, or by endogenous, dietary intake. Vitamin D is then
hydroxylated by 25-hydroxylase in the liver, and 1-hydroxylase in the
kidney to form 1,25 D.
a. Renal activation of vitamin D to a hormone: 1,25 D formation is
stimulated in the kidney to form the most potent form of vitamin D. It
is considered to be a hormone due to its regulation, chemical structure,
and method of action.
2.
Calciotropic hormones actions and biochemical mechanisms in:
a.
Bone:
a. PTH increases serum Ca2+ and PO4 by increasing osteoblastic cAMP
activity via Gs. This causes an increase in urinary excretion of PO4,
increased osteoclast activity via IL-6, and increased osteoclast
differentiation via ODF.
b. 1,25 D binds to the nuclear vitamin D receptor which heterodimerizes
with the RXR receptor to increase gene transcription of IL-6, ODF,
and osteocalcin (a protein that binds to bone and promotes osteoclast
accumulation)
c. Calcitonin decreases serum Ca2+ and PO4 by increasing osteoclastic
cAMP activity via Gs. This mainly inhibits PTH signaling and
activation of osteoclasts, and reduces osteoclast activity.
b.
Kidney: PTH increases serum Ca2+ and PO4. 1,25 D increases serum
Ca2+, but a decrease in serum PO4.
c.
Intestine: 1,25 D increases serum Ca2+ and PO4 by translating an apical
Ca2+ channel, a Ca2+ binding protein, and a basolateral Ca2+/ATPase to
increase reabsorption of intestinal calcium.
3.
Bone mineral:
a.
Laid down to strengthen endoskeleton: bone mineral is composed of
hydroxyapatite which is laid down on a collagen matrix to strengthen the
endoskeleton.
b.
Mobilized to maintain serum Ca2+: bone mineral is broken down to
release Ca2+ from hydroxyapatite and increase serum Ca2+ levels.
4.
Pathophysiology of:
a.
Humoral hypercalcemia of malignancy: produces a PTH-like peptide
hormone that is not feedback inhibited by Ca2+. Therefore, there is an
increase in Ca2+ mobilization from bone and subsequent hypercalcemia.
b.
Pseudohypoparathyroidism: inactivity of the s subunit and a subsequent
diminished response to PTH. Presents clinically with short stature, round
face, brachydactylia, subcutaneous calcification, and mental deficit (due to
the other pathways (GH, TSH, glucagon, etc.) use of the Gs second
messenger.
c.
Nutritional rickets: caused by a lack of nutritional vitamin D and sunlight
exposure; hypocalcemia and hypophosphatemia inhibits hydroxyapatite
deposition to strengthen bone.
d.
Renal osteodystrophy: caused by a lack of 25 D conversion to 1,25 D;
lack of 1,25 D causes hypocalcemia and hypophosphatemia and weak
bones.
e.
Hereditary rickets:
a. Type I: caused by a renal 1-hydroxylase deficiency that can be treated
by administering exogenous 1,25 D.
b. Type II: caused by a defect in the vitamin D receptor.
5.
Hormone binding defect in vitamin D receptor treatment: can be treated by
extremely high doses of 1,25 D to overcome low receptor affinity to 1,25 D.
DNA binding domain defect in vitamin D receptor treatment: cannot be
treated by 1,25 D since 1,25 D binding is fine.