Lecture 16 - micronutrients part 3 Flashcards
What are some dietary sources of niacin?
fish, meats, breads and cereals, coffee and tea
What is another word for niacin?
vit B3
In plant foods, how is vit B3 or niacin found?
as nicotinic acid
What is nicotinic acid
provitamin of niacin/vitB3
Where is deficiency of niacin seen a lot?
in areas where corn is the main dietary staple, because niacin is attached to indigestible carbohydrates in corn, therefore it is poorly absorbed
In animal derived foods, how is vit B3 found as?
nicotinamide
nicotinamide adenenine dinucleotide (NAD)
nicotinamide adenine dinucleotide phosphate (NADP)
How can niacin be produced in the body?
produced in the liver from the AA tryptophan (but only 1/60th of tryptophan is converted to nicotinamide
Does niacin need to be digested?
NAD and NADP require digestion before absorption
How is niacin digested?
NAD and NADP are hydrolyzed by the glycohydrolase enzyme to release free nicotinamide
Where are nicotinic acid and nicotinamide absorbed?
a bit in the stomach, but most is absorbed in the small intestine through facilitated diffusion
How does niacin circulation in blood plasma?
as free nicotinamide
Can niacin pass through membranes?
yes, nicotinic acid and nicotinamide can cross cell membrane by simple diffusion in most tissues, except kidney and RBC’s
What are the precursors for NAD and NADP in the body?
nicotinic acid and nicotinamide
What happens to niacin once NADP is synthesized?
niacin is essentially trapped within the cell
What are the reduced forms of NAD and NADP?
NADH
NADPH
What is the function of NADH?
the transfer of electrons to the ETC
What is the function of NADPH?
a reducing agent in biochemical pathways
What are the two steps from nicotinic acid to be converted to NADP?
- convert the acid to an amide
- build into a dinucleotide instruction: contains a sugar (ribose) a nitrogenous base and a phosphate
When is NAD+ reduced to NADH?
- glycolysis
- krebs
- B-oxidation
- catabolism
When is NADP+ reduced to NADPH?
- hexose monophosphate shunt
Why is NADP+ reduced to NADPH?
- FA synthesis
- glutathione regeneration
- anabolism
How many electrons do NAD and NADP accept?
2
What is the issue with corn and niacin absorption?
- corn contains significant amounts of niacin, but it’s bound and not absorbed
- also is deficient in tryptophan
How can niacin be released from corn?
use of lime (from limestone) helps to release niacin from corn
What does niacin deficiency lead to?
pellagra: dermatitis, dementia, diarrhea, death
- most symptoms are reversible
Do RDA requirements for niacin include the small amounts of tryptophan?
yes
NE
niacin equivalents
What is the NE formula?
NE = mg preformed niacin + mg Trp/60
What foods is riboflavin found in?
- milk, milk products meat
- other foods contain flavins, found as either flavin mononucleotide (FMN) or flavin adenine dinucleotide (FAD) which are essentially bound to riboflavin
FAD
flavin adenine dinucleotide
FMN
flavin mononucleotide
What is riboflavin degraded by?
sunlight (which is why milk is no longer sold in glass bottles
What is another term for riboflavin?
vit B2
How is riboflavin digested?
riboflavin that is bound to proteins must be released prior to its absorption, this is done by HCl (protein denaturation) in the stomach
How is riboflavin absorbed?
from the gut lumen by an active transport mechanism known as the riboflavin transporter 2 (RFT2)
RFT2
riboflavin transporter 2
How are riboflavin, FAD and FMN transported in the body?
bound to proteins - albumin
Where is riboflavin stored in the body?
liver, kidneys, heart, extra is usually excreted in the urine
How long do sufficient amounts of riboflavin last when no longer consumed in the diet?
2-6 weeks
Where are FMN and FAD made?
in the cells
What is the primary form of riboflavin in the body?
FAD - 60-95%
What is production of riboflavin positively regulated by?
T3 hormone, which increases the activity of the flavokinase enzyme
How is riboflavin metabolized into FMN and FAD steps?
- riboflavin becomes riboflavin PO4 flavin mononucleotide (FMN) through the enzyme flavokinase (Mg2+ or Mn2+) turning ATP into ADP
- FMN can convert to FAD through the enzyme FAD synthetase (Mg2+ or Mn2+) again, turning ATP into ADP
What is the structure of riboflavin?
ribotol - linear ribose
flavin - nitrogenous base
What is FMN considered?
nucleotide:
base + sugar + P
What is FAD considered?
dinucleotide:
FMN + adenine + sugar + P
What is the redox for FMN?
FMN -> FMNH2
reduction
2 e- transfer
What is the redox for FAD?
FAD -> FADH2
reduction
2 e- transfer
What is the difference between FMN FAD and NADP?
function similarly in electron transfer, the primary difference is that FMN and FAD are typically bound to the active site of an enzyme
What are the steps to riboflavin in redox of GSSG to GSH?
GSSG + NADPH -> 2GSH + NADP+
O R R O
enzyme: glutathione reductase
FAD -> FADH2 when NADPH -> NADP+
FADH2 -> FAD when GSSG -> 2GSH
- to regenerate glutathione, FAD accepts 2 electrons from NADPH, temporarily becoming FADH2
What does reforming glutathione require?
both niacin (NADP) and riboflavin (FAD)
What occurs if there is a riboflavin deficiency?
ariboflavinosis
What are the symptoms of ariboflavinosis?
- signs of deficiency appear within 3-4 months
- deficiency relatively common when dietary intake is insufficient because riboflavin is continuously excreted in the urine
- reversible
- cracked and red lips, inflammation of the lining of the mouth and tongue, mouth ulcer, cracks at the corner of the mouth
What are the populations at risk for deficiency?
- people with hypothyroidism or thyroid disease, because they can’t make thyroid hormones to activate flavokinase
- chronic alcoholism, which reduces riboflavin digestion and absorption
- people who are lactose intolerant (reduced consumption of dairy foods and beverages)
Is there an upper limit for riboflavin?
no
What foods is thiamine found in?
meats, whole fortified or enriched grain products
How is thiamine destroyed?
heat and alkaline environment
How does thiamine exist in plants?
thiamine provitamin exists in a free form
What is antoher term for thiamine?
vit B1
How does thiamine exist in animals?
phosphorylated form (TPP) - active form
What is the active form of thiamine?
TPP
TPP
thiamine pyrophosphate
How is thiamine absorbed?
phosphate group but be removed to allow for its absorption, controlled by thiamine transports
Where is thiamine absorbed?
in the small intestine
How is thiamine found in blood plasma?
TPP is found in free form or bound to albumin
How is TPP produced (thiamine metabolism) steps?
thiamine (plant provitamin) is converted to TPP (active form) through the enzyme thiamine diphosphokinase and converting ATP to AMP
- adding two phosphate groups
What does TPP contain in its structure?
two phosphates and a carbanion
What key oxidative decarboxylation steps is TPP important in?
- pyruvate dehydrogenase complex
- alpha-ketoglutarate dehydrogenase complex
- these enzymes also require FAD, NAD and CoA as cofactors
- critical in the movement of sugars and AA into energy metabolism pathways
In what non-oxidative cycle is thiamine required in?
in the non-oxidative phase of the hexose monophosphate shunt - plays a role in the synthesis of nucleotide precursors
What does thiamin deficiency cause?
critical energy metabolism pathways
- prevents ATP production and acetyl-CoA synthesis
- causes accumulation of pyruvate, lactate and alpha-ketoglutarate in blood
What are the health implications of thiamine deficiency?
- dry beriberi: predominantly in adults due to chronic low thiamine intake, muscle weakness, affects the nervous system
- wet beriberi: predominantly in children and young adults, more severe than dry beriberi and affects the cardiovascular system
- acute beriberi: occurs primarily in infants, anorexia, vomiting, lactic acidosis, and eventually death if left untreated
Who is more susceptible to thiamine deficiency?
chronic alcoholism
people depending on polished white rice as a major source of food
Is there an upper limit for thiamine?
no
What foods is pantothenic acid found?
present everywhere
What is another term for pantothenic acid?
vit B5
How does pantothenic acid occur in foods as?
ubiquitously in foods in both free and bound forms, mostly occurs as part of coenzyme A (CoA)
Is there deficiency or toxicity associated with pantothenic acid?
no, because it is present in all foods
How is pantothenic acid absorbed?
passive diffusion
Where is pantothenic acid absorbed?
jejunum
How is pantothenic acid found in blood plasma?
found free
How does uptake of pantothenic acid into tissues occur?
through the sodium-dependent multivitamin transporter (SMVT)
SMVT
sodium-dependent multivitamin transporter
Pantothenic acid acts as the precursor in the synthesis of what molecule?
coenzyme A
How is pantothenic acid converted to coenzyme A steps? (metabolism)
- pantothenic acid is converted to 4-phosphopantetheine using cysteine, phosphate (from ATP) and CO2 as cofactors
- 4-phosphopantetheine is converted to coenzyme A (CoA, CoASH) using AMP -> PPi as a cofactor
What is 4-phosphopantetheine
an intermediate, the active form of pantothenic acid in fatty acid synthesis, important component of acyl-carrier protein in the fatty acid synthase complex
What is coenzyme A (CoA, CoASH)
active form of pantothenic acid in oxidative reactions, energy production, formation of acetyl CoA
What are the sources of biotin?
- made by intestinal bacteria: although not enough is made to meet the needs of humans
- widely found in foods bound to proteins
What is biotin attached to?
protein called avidin, when attached, no absorption occurs
How is biotin digested?
must be removed from proteins prior to its absorption, proteolysis by pepsin in the stomach breaks down proteins and released biotin
How is biotin absorbed?
free biotin is absorbed to near completion, alcohol inhibits biotin absorption
How does biotin circulate in blood plasma?
in the free form (80%) with a bit bound to albumin
What is another term for biotin?
vit B7
Are there RDAs or deficiency in place for biotin?
no because its so prevalent
What are the steps to biotin-mediated carboxylation?
rxn #1:
biotin with biotin ring has a carboxyl group that interacts with NH2 group of a lysine s.c. in an enzyme via a peptide bond
carboxylation of the N in the biotin ring structure occurs with HCO3- and ATP as cofactors
rxn #2:
the carboxyl group is then transferred to another molecule
What is the structure of biotin?
two rings (with Na dn S) and a s.c. with a carboxyl group
What are the 3 key reactions involving biotin?
- pyruvate carboxylation - production of oxaloacetate
- malonyl CoA formation
- conversion of propionate into glucose (important in ruminants)
What is another term for folate?
vit B9
What is folate referring to?
generic term that refers to both natural folates in food and the synthetic form used in supplements and fortified foods called folic acid
Are folate and folic acid structurally different?
yes
- folic acid refers to the oxidized form of the vitamin found in fortified foods and supplements - 100% bioavailable
- folate refers to the reduced form of the vitamin found naturally in foods - 50% bioavailable
What are the three parts that folate is composed of?
pterin ring
PABA
glutamic acid
PABA
para-aminobenzoic acid
Can humans synthesize all three components of folate?
yes, however lack the enzymes to conjugate them
What is folate critical for?
production of nucleic acid precursors and several AA, as well as methylation reactions, important in bone marrow and developing fetus
What must occur in folate before absorption?
natural folates have multiple glutamate residues which must be removed for absorption in its simplest form
How is folate digested?
polyglutamate hydrolase removes the glutamate residues
How is folic acid digested?
folic acid is already a mono glutamate structure, so no digestion is required
How/where is folate absorbed?
through a proton-coupled folate transporter (PCFT) in the small intestine
PCFT
proton-coupled folate transporter
What is folate and folic acid usually converted to in the small intestine?
converted into the bioactive compound 5-methyltetrahydrofolate (5-methyl THF)
What form of folate do you generally detect in blood plasma?
mostly 5-methyl THF and a bit of folate
How is folate transported in blood plasma?
bound to protein, such as albumin
What is the bioactive form of folate?
5-methyl THF
What is the structural difference between folic acid and folate?
folic acid - only 1 glutamate residue
folate - multiple glutamate residues
DFE
dietary folate equivalent
What is the formula for DFE?
Total DFE = microg food folate + (1.7 x microg folic acid)
What is absorbed more folic acid or folate?
folic acid
Why is folate toxicity a risk?
very easy to exceed the UL if taking supplements and eating fortified foods, too much folate can lead to increased cancer risk
What is another term for cablamin?
vit B12
What is vitamin b12 a generic term for?
a group of compounds called corrinoids (because of corrin nucleus that contains cobalt)
What is unique about vitamin B12 structure?
cobalt in the corrin nucleus, the most complex vitamin structure and is unique in that it contains a metal ion
What produces vit B12?
only bacteria, spoilage of meat can increase vit B12
Where is vitamin B12 present?
animal products
Is there a plant provitamin B12?
no, so vegetarians and vegans are at risk
What does a vit B12 deficiency cause?
functional deficiency for folate, neurological problems
What does B12 work with?
folate
is there an upper limit for vit B12?
no
What are the steps to absorption of vit B12?
- when B12 enters the stomach, a specific binding protein is secreted from the gastric lining known as IF (intrinsic factor)
- binds to B12
- the B12-IF complex goes to a receptor in the small intestine
- the complex is broken down in the enterocyte and vitB12 is absorbed while IF is released back into the intestinal lumen, it is either attached to another B12 or excreted
Where does B12 usually go after absorption?
Vit B12 is stored in the liver and can undergo enterohepatic circulation
- high storage in the liver so deficiencies can take years to surface
What are the two causes of a vit B12 deficiency?
- not enough in your diet - in strict vegans (resolved with megadoses of vitB12)
- improper absorption due to defects in IF - deficiencies shown in blood in the form of megaloblastic anemia
What are the steps to the single carbon metabolism?
- dietary folates enter the blood stream through the removal of polyglutarate s.c. and a methylation at N5 becomes N5-methyl THF
- N5-methyl THF (bioactive folate) goes to an organ tissue
- N5-methyl THF is converted to THF where cobalamin receives a methyl from folate and becomes methyl-cobalmin, this is mediated by the methionine synthase enzyme
- methyl cobalamin gives its methyl group to homocysteine which turns it into methionine (enters SAM cycle)
- methionine becomes S-adenosyl methionine, it gives its methyl a substrate to become S-adenosyl homocysteine and goes back to homocysteine
- back to THF, CH3 (usually serine) gives its methyl group to THF to convert it to N5N10-methylene THF
- N5N10-methylene THF can go back to THF for regulation or can go into dUMP -> dTMP-> dTTP for DNA synthesis regulated by the enzyme thymidylate synthase
- dTTP goes into the nucleus to partake in DNA synth and cell division
What does the SAM cycle help with?
DNA synthesis
What is the folate trap?
when someone is B12 deficient, the single carbon metabolism is affected:
- N5-methyl THF is trapped and can’t become THF
What is the issue with the folate trap?
large doses of folate form supplements can hide a vitB12 deficiency, so you get more folate going to the liver where is it converted into THF, however there is a still a problem with the SAM cycle
What are the health implications of a folate deficiency?
- folate is important for dividing cells
- it supports the production of specialized cells that form the neural tube - takes place during early pregnancy
- folate deficiency leads to severe birth defects
- in the embryo neural tube is the CNS which becomes brain and spinal cord - defects can occur with these
- closed vs open NTD - open is more common, the brain and spinal cord are exposed
What does vitamin B6 exist as?
6 vitamers - interchangeable and comparably active - all can be found phosphorylated or unphosphorylated
What are some vitamers of vit B6?
pyridoxine - plant provitamin
pyridoxal
pyrixoxamine
What foods is B6 found in?
all isomers are found in foods, deficiency is very rare
What demands more B6?
high protein intake to support transamination
What must be done to B6 before absorption?
dephosphorylation
How and where is B6 absorbed?
passive diffusion in the jejunum
What is the main form of B6 found in the blood?
PLP, bound to albumin
Where are high levels of B6 found in the body?
In the muscle
How is vitamin B6 metabolized steps?
occurs primarily in the liver
1. pyridoxine (alcohol) - plant provitamin is converted to pyridoxal (aldehyde)
2. pyridoxal is converted to pyridoxal phosphate - PLP - active cofactor
What is the important of PLP in body function?
- cofactor for many enzymes including aminotransferases
- also involved in the first step in porphyrin synthesis
- synthesis of neuroactive aminoes
What does B6 deficiency cause
microcytic anemia
What are the three types of anaemia?
- megaloblastic anaemia
- hemolytic anaemia
- microcytic anaemia
How can anaemia occur?
stem cells in bone marrow are differentiated in the presence of erythropoietin, normally differentiation causes RBC’s to shrink, nucleus is removed and able to carry O2, process is very sensitive to micronutrient deficiencies, which leads to anaemia
How does megaloblastic anemia occur?
folate and vit B12 deficiencies - issues with DNA synth
pro erythroblast undergoes DNA synth forming a reticulocyte RBC
- RBC’s are packed with hemoglobin and cause bigger cells
How does hemolytic anemia occur?
vit E, selenium and cysteine deficiencies - oxidant stress
causes premature breakdown of RBC’s
How does microcytic anemia occur?
vitB6 deficiency - hemoglobin production causes RBC’s to not be able to make porphyrin ring which means less hemoglobin and paler cells
