Nutr 302 Quiz 2

• Chemical Characteristics of Calcium

  • 2 valence electrons; lost readily in solution creating Ca2+
  • Ca2+ (preferred state), tight configuration (low ionic

  radius), attracts H2O and has unique properties of a

  large ‘effective ionic radius’.

  • Intracellular movement of Ca2+ is limited due to the

  permeability of the membrane.
• Ca2+ ‘useful’ due to interaction with other ions & proteins

  within the cell (voltage gated channels specific for Ca2+ )

  ¡ The binding constant of Ca2+ can change, interacts

  with array of different molecules
• Biological functions of Calcium?

  Generally Ca2+ is considered a tool or carrier

  (messenger); does not necessarily cause the function

  itself but can initiate series of processes

  • Intracellular concentration of free Ca2+ (cytoplasm) is

  very low (<0.01% of extracellular fluid) – maintained

  by pumps

  • Cell activation by depolarization, neurotransmitters,

  hormones & second messengers results in Ca2+

  entering cytoplasm extracellularly or intracellularly

  • Rapid rise and fall in cytoplasmic Ca2+ allows function to be performed
• Biological Functions of Calcium

  • Bone mineralization

  l Component of bone & teeth as hydroxyapetite

  l 99% of calcium (& 80-90% of phosphorus) is mineralised in bone
• ¡ Of the remaining 1%, ~half is as ionized Ca2+ (active form)...

  l Increases in intracellular calcium (cytosolic) - may act on cell

  directly or via calcium binding proteins to regulate processes such

  as blood clotting, nerve conduction, muscle contraction, enzyme

  regulation, membrane permeability,
• Ionized Ca2+ examples?

  ¡ Platelet PLA2 - hydrolyzes AA from PL in cell membranes to form

  prostaglandins, thrombboxanes, leukotrienes

  ¡ Protein kinase C - phosphorylates enzymes that stimulate/inhibit

  metabolic pathways

  ¡ Calmodulin - binds 4 Ca2+ & changes conformation/ability to interact

  with calmodulin-dependent enzymes such as calcineurin &

  phosphorylase kinase
• (Indirect influx of Calcium by changing intracellular

  electrical properties of membrane)
• (Agonist dependent calcium channel -as a second

  messenger – Pathway – Ligand Binding)
• (Impact of intracellular Ca2+ influx and Calmodulin)
• (Inositol triphosphate (IP3) messenger pathway and Ca2+ release)

  • PI is phosphorylated to

  form PIP, PIP2 & PIP3

  • IP3 (made by hydrolysis of

  PIP2) & DAG are second

  messengers used in signal

  transduction and lipid

  signaling

  • DAG stays in membrane

  • IP3 is soluble & diffuses

  through cell
• Chemical Characteristics of Phosphorus

  ¡ Unique property of Phosphorus is that the

  preferred ionic state (in solution) is

  orthophosphate as HPO4

  ¡ At pH 7.4 ratio is 4:1

  ¡ Acts as a buffer

  ¡ Majority of phosphorus stores in the body are

  found in bone as hydroxyapatite Ca10(OH)2(PO4)6
• Biological Functions of Phosphate?

  ¡ Bone mineralization

  ¡ Electrolyte homeostasis, acid-base balance

  ¡ Structural role

  ¡ DNA/RNA structure based on phosphate ester monomer

  ¡ Phospholipids (phosphate head group)

  ¡ Energy storage and transfer (ATP)

  ¡ Second messenger

  ¡ Phosphorylation of proteins (kinases) & de-phosphorylation

  (phosphatase) essential to molecular regulation

  ¡ Metabolic trapping reactions by phosphate esters e.g

  Vit B metabolism
• Phosphate alternates

  with pentose sugars

  to form linear

  backbone of nucleic

  acids DNA and RNA
• Biological Functions of Phosphate

  (ATP and energy release)

  Energy storage and transfer (includes nucleotides & derivatives)

  o Forms high energy phosphate bonds used in intermediary

  metabolism such as those in ATP, creatine phosphate, UTP and GTP... Also NADP
• Biological Functions of Phosphate

  (Intracellular second messenger)

  ¡ Part of cyclic adenosine monophosphate (cAMP),

  derived from ATP in response to hormone-receptor

  binding, activates protein kinases

  l Many enzyme activities are controlled by phosphorylation

  and dephosphorylation

  ¡ Inositol triphosphate (IP3) acts to trigger intracellular

  Ca2+ release as mediated by protein kinases
• Calcium Absorption (typically only 20-30% effective)

  ¡ Transcellular (major route) – saturable, requires energy + channel

  + binding protein (calbindin), stimulated by low Ca diets &

  calcitriol (genomic mechanism) ⇝ mostly duodenum

  ¡ Paracellular – non-saturable, energy independent (passive),

  concentration dependent ⇝ mostly ileum/jejunum

  ¡ Colonic fermentation of fibres may release Ca2+ (4-10% of
• Phosphate absorption (60-70% effective)

  ¡ Absorbed linearly to intake, preference as HPO42-, mechanism

  similar to Ca2+ but little is known about the details

  ¡ Twice as efficient as Ca2+ absorption, responds to calcitriol but less so than Ca2+
• Parathyroid hormone (PTH) is secreted by the parathyroid glands
• Calcitonin is secreted by the thyroid gland
• ¡ Parathyroid Gland - plasma Ca2+ feedback mechanism controls

  PTH production and secretion

  ¡ PTH - peptide hormone produced by parathyroid gland, acts on

  cell surface receptors

  ¡ Acts primarily on the bone (osteoblasts) and kidney (tubular cells),

  often indirectly via second messenger systems
• Kidney tubular cells respond to PTH ð ⇧re-absorption of Ca2+ but

  simultaneously ⇩ re-absorption of phosphate ð ⇧urinary excretion

  ¡ PTH regulates conversion of vitamin D to active form in kidney

  ¡ 25-Hydroxyvitamin D or 25(OH)D hydroxylated by the enzyme 1a-

  hydroxylase into the main biologically active hormone 1,25-

  Dihydroxyvitamin D or 1,25(OH)2D or Calcitriol
• Calcitonin

  • Peptide hormone secreted from the thyroid gland
  • Released when Ca2+ is high (PTH is when low)
  • ¡ Opposite effects of PTH, Calcitonin increases bone
  • mineralization and deposition of Ca+2 (storage) and
  • reduces Ca+2 absorption from the kidneys
• Bone Remodelling

  ¡ ~10% of skeletal bone mass replaced every year in adults

  (complete structural overhaul every decade) due to

  constant remodelling

  • Allows bone to support the body/allow movement, incubate

  developing immune cells, & act as a reserve of inorganic minerals
• ¡ Remodelling repairs bone defects and helps maintain

  optimal levels of calcium in the blood

  ¡ Osteoclasts destroy and resorb old bone and osteoblasts

  deposit new bone in its place

  l Carefully controlled cycle - slight imbalance between bone

  destruction and formation can lead to decreased bone density and

  osteoporosis

  
  

  => Bone resorption & formation are “coupled”
• Bone remodelling cycles

  1. Pre-osteoclasts
  2. active osteoclasts
  3. Resorption
  4. mononuclear cells
  5. reversal
  6. pre-osteoblasts
  7. bone formation
  8. osteoblasts
  9. osteocytes
  10. mineral lization
• Resorption = 40 days

  Mineralization = 145 days
• Activation phase involves

  conversion of osteoclast precursor

  cells to active osteoclasts

  • Reversal phase allows transition

  from bone resorption to formation
• Calcium & Phosphorus Urinary Excretion?

  Unlike Ca2+, phosphorus absorption has a linear

  relationship with urinary excretion

  l Kidneys regulate Phosphate well, do not regulate Calcium

  as well (binds to albumin ∴ cannot enter filtrate)

  ¡ Most renal reabsorption of phosphorus at proximal tubule

  by an active sodium-phosphate cotransporter

  ¡ Most renal reabsorption of Ca2+ is paracellular at various

  parts of the nephron

  l Urinary Ca2+ & Na+ losses associated due to reabsorption

  of both in parallel with water movement
• Factors affecting Calcium Absorption & Excretion?

  ⇧Absorption = calcitriol, sugars, protein

  ¡ ⇩Absorption = fibre (binds), phytate (binds), oxalate

  (chelates), excess divalent cations (Zn, Mg) (competes), excess

  unabsorbed fatty acids (forms soaps)

  ¡ ⇧Ca Urinary excretion = sodium, protein (sulfur AAs), caffeine

  ¡ ⇩Ca Urinary excretion = ⇧plasma phosphate ð⇩ionic Ca2+ ð

  ⇧PTH synthesis ð ⇧Ca2+ reabsorption

  ¡ Absorption of nutrients (e.g iron, fatty acids)⇩ by excess Ca2+

  ¡ Ca2+ supplements are as calcium chelates, i.e. calcium citrate,

  gluconate or carbonate - absorption varies (25-35%)
• Increase in Urinary excretion of Phosphorus can be caused by increasing circulating phosphate or calcium, PTH, estrogen, thyroid hormones, and phosphatonins, which inhibit reabsorption.
• Increase in Phosphate loss can be achieved by FGF-23 secreted from osteocytes in bone, which suppresses the expression of sodium-phosphate cotransporters.
• Calcium Bio-availability?

  Affected by

  fibre, phytate,

  oxalate, protein
• Calcium requirements over the life cycle

  • Formula-fed infants - reduced Ca2+ bioavailability due

  to lack of growth factors that aid uptake in breast

  milk, also due to phytates in soy isolates

  • Infants (0-12 months) - need to achieve Ca2+

  retention to support bone growth peak rate of

  growth during puberty

  • Post-Menopausal women need to ensure adequate

  retention of bone mass to avoid deficiencies and Ca2+

  loss in later stages
• Food Sources of Calcium?

  • Majority of Ca in NA

  diets is from milk &

  milk products

  • Non-dairy sources

  include calcium-set

  tofu & some green

  vegetables

  • Calcium fortified foods

  are now available
• Sources of Phosphorus & DRIs over the life cycle

  • AIs for Infants - based on mean intakes of breast-

  fed infants

  • RDAs are based on EAR + 20%

  – In children: estimated using body accretion corrected

  for absorption efficiency, urinary losses - must retain

  P for bone growth

  – Criteria for adequacy in adults = serum concentration

  • Pregnancy and Lactation - No evidence for

  increased requirements
• Food Sources of Phosphorus

  • Widely distributed

  • Protein sources (meat, milk,

  eggs, cereals) usually high

  in P

  • Diary products, meat, fish,

  poultry & eggs supply ~70%

  of typical intakes

  • Processed foods & soda

  contain P as additives
• Calcium/Phosphate Deficiencies:

  Disorders:

  • Intestinal disorders - Crohns disease - with marked fat mal-

  absorption

  • Chronic liver disease - Vit D metabolism

  • Kidney - renal disease ð ⇩ Vit D + re-absorption problems (Ca2+

  leaks out, P kept in)
• Inverse association between dietary Ca2+ & risk of hypertension (altered salt and calcium intake exert reciprocal effects on these hormone systems and on blood pressure).

  • Abnormal (decreased turnover) calcium metabolism in pre-eclampsia ( intracellular Ca2+, ATPase activity [⇩ efflux])
• Osteoporosis: Peak bone mass & retention of bone may be related to Ca2+ intake &/or other factors (height, weight bearing, PTH, estrogen) => Bone health as a 3-legged stool
• Calcium depletion is difficult to assess, confounded by other

  causes, i.e. Vit D deficiency, bone diseases & other hormonal

  imbalances (similar symptoms)

  • Dietary Ca restriction ð PTH, 1,25(OH)2D, Ca & P intestinal

  absorption, Ca & P urinary excretion, bone resorption,

  turnover & loss