Midterm (Lec 5) Flashcards
Folate
Initially discovered as a growth factor in green leafy vegetables ”foliage”
Folate forms in foods and body
Supplemental form in fortified foods and supplements is folic acid
Chemical name is pteroylglutamate/pteroylglutamic acid
Number of glutamates varies from 5-8 ; need it at 1 to absorb LOOK AT STRUCTURE
Folate absorption
Majority of food folates are polyglutamates
Must be cleaved to mono glutamate for absorption
Allows folate to be absorption
Many drugs compete with folate
- inhibit absorption
- compete for transport
Folate transport
Folate binding proteins (usually don’t need binding proteins for B vitamins)
Identified in plasma and other tissues
Bind folate with high affinity
Transports folate to liver and other cells
Cells store folate by adding back glutamates (can’t be stored without glutamate)
Folate Coenzyme
Needs to be converted to its coenzyme form o perform metabolic roles TETRAHYDROFOLATE
Activated by reduction (adding hydrogens) - added to positions 5,6,7,8
Folate -> dihydrofolate -> tetrahydrofolate (THF)
Dihydrofolate reductase is the enzyme
Niacin adds H to folate
THF
- fully reduced state
- must be in this form to carry carbon units and perform metabolic role
— ONE CARBON UNITS added to THF
Folate metabolic role: single carbon metabolism
Calling card of folate (THF)
Acceptor and donor of 1-carbon units
Important in:
- amino acid metabolism
- nucleotide metabolism
Ex: methyl group CH3
- transfer of methyl groups involved in many reactions
- folate central in methyl group transfer
-recall other carbon groups that are transferred by THF
Folate: amino acid metabolism
Methionine Synthesis
- involved homocysteine (hcy to met)
- Folate deficiency will build up homocysteine
- also needs B12
Histidine catabolism
- basis for a folate deficiency test: FIGLU LOAD TEST
interconversion of serine and glycine
- serine OH methyltransferase
- needs B6
Nucleotide metabolism
Synthesis of purines and pyrimidines
- heterocyclic nitrogenous compounds
- purine (adenine, guanine) and pyrimidine bases (uracil, thymine, cytosine)
Allow synthesis of nucleosides and nucleotides
- ex: ATP - a nucleotide synthesized from purine
DNA synthesis
- needed for DNA synthesis (key focus for folate)
- crucial for cell division and growth
- ex: folate acts as a coenzyme for enzyme involved in DNA synthesis:
——— thymidylate synthetase (key enzyme)
All involve transfer of one carbon units
Methotrexate
Chemotherapy drug
Inhibits DHFR - dihydrofolate reductase
- decreases THF therefore less DNA synthesis and less cancer cell replication
Folate food products
Dark green vegetables
Fortified products
- folic acid in white flour, pastas, corn meal
Folate deficiency
due to diet, drugs, or malabsorption
Same anemia as B12 deficiency
Weakness, depression
Increased homocysteine
NEURAL TUBE DEFECTS - birth defect
Folate can mask B12 deficiency
You will have macrocytic anemia with either b12 or folate deficiency
Supplements of either will correct the anemia BUT not other symptoms
Aka if you have inadequate B12 with adequate folate your will NOT see anemia
- fortified foods could be causing B12 deficiency by masking symptoms
Diagnosing folate deficiency with FIGLU
Also called histidine load test
Method to diagnose folate deficiency
- give excess histidine
- 24 hour urine collection/blood sample
- measure FIGLU in urine OR blood
- if high = folate deficiency
Dietary folate equivalents
Folate: in food
Folic acid: in fortified foods and supplements
Bioavailability ranking
1. Supplemental folic acid on an empty stomach
2. Fortified foods
3. Foodfolate (lowest since it’s bound to other food components)
Folate and NTDS
Folic acid supplementation reduces risk of neural tube defects
Event occurs when tube is closing (21-28 days post conception)
Women should always be supplementing with folate but our flour is fortified (could contribute to masked B12 deficiency?)
Folate can decrease cancer risk
Folate plays a key role in proper DNA and RNA synthesis as well as genetic stability
Folate intake related to decreased cancer risk (colorectal most evident)
Folate can increase cancer risk
Folate can also facilitate multiplication of cancer and pre cancerous cells (high proliferation rate)
Cancer cells need folate to maintain thymidine synthesis at a pace needed to maintain high DNA synthesis
CORE ISSUES:
- timing of exposure (better in beginning of life vs later bc you could have pre cancerous cells already)
- level of exposure (too much or too little)
- form of exposure (folate vs folic acid)
Homocysteine
Intermediate of methionine metabolism
Not present in the diet + not incorporated into protein
Associated with CVD
Possible role in dementia and Alzheimer’s
Homocysteine fates
3 fates
- remethylation to methionine (needsfolate, B12, choline)
- transulfuration to cysteine (needs B6)
- release into circulation
Example of inter relationships among nutrients to optimize human health
Choline
Nutritional importance discovered when animals fed choline free diet developed fatty liver disease which resolved when fed choline
TPN without choline induces symptoms: fatty liver and liver damage, resolved when choline added
Choline structure
Simple structure
Serves as methyl group donor - can be synthesized from methionine
Choline then synthesized to:
- phosphatidylcholine
- acetylcholine
- betaine
RECOGNIZE STRUCTURE
Choline metabolic role
Precursor for phosphatydilcholine
- phospholipid
- essential part of all cell membranes
- membrane structure and fluidity
- lipid transport (lipoproteins) : packages them up (we would have lipid build up and fatty liver without this)
- CHOLINE OCCURS AS PHOSPHATYDILCHOLINE / LECITHIN IN FOOD
Precursor for acetylcholine
- neurotransmitter
- muscle control, memory
Precursor for betaine
- transmethylation reactions
- single carbon metabolism
- needed to convert homocysteine to methionine (+ b12 and folate)
Choline deficiency
Can be synthesized in our body and widely present in foods
Deficiency signs:
- elevated liver enzymes (sign of liver dysfunction)
- fatty liver
Choline and cognitive function
Correlated since choline is a precursor for acetylcholine
Early life choline can diminish severity of memory deficits in later life
- role for Alzheimer’s? (Patients have a low conversion of choline to acetylcholine in the brain) only moderate improvements have been seen with lecithin
Choline and cancer
Choline deficiency associated with increased liver cancer and increased sensitivity to liver carcinogens in rats (no human data)
Relation to fatty liver damage from choline deficiency
Choline and CVD prevention
Choline as a precursor to betaine
Involved in reducing homocysteine in the blood
Works with folate and B12
Too much choline
TMAO: Trimethylamine N-oxide
TMAO is a metabolite of choline that is produced from intestinal bacteria
TMAO has been associated with INCREASED risk of heat disease
TMAO is Ana drive area of research in relation to other areas of health as well
