Chapter 100. Megaloblastic Anemias (Part 3) docx

The total folate content of an average Western diet is ~250 µg daily, but the amount varies widely according to the type of food eaten and the method of cooking.. Daily adult requirement

Chapter 100 Megaloblastic

Anemias (Part 3)

Most foods contain some folate The highest concentrations are found in liver, yeast, spinach, other greens, and nuts (>100 µg/100 g) The total folate content of an average Western diet is ~250 µg daily, but the amount varies widely according to the type of food eaten and the method of cooking Folate is easily destroyed by heating, particularly in large volumes of water Total-body folate in the adult is ~10 mg, the liver containing the largest store Daily adult requirements are ~100 µg, so stores are only sufficient for 3–4 months in normal adults and severe folate deficiency may develop rapidly

Absorption

Folates are absorbed rapidly from the upper small intestine The absorption

of folate polyglutamates is less efficient than for monoglutamates; on average,

~50% of food folate is absorbed Polyglutamate forms are hydrolysed to the monoglutamate derivatives, either in the lumen of the intestine or within the mucosa All dietary folates are converted to 5-methylTHF (5-MTHF) within the small-intestinal mucosa before entering portal plasma The monoglutamates are actively transported across the enterocyte by a carrier-mediated mechanism Pteroylglutamic acid at doses >400 µg is absorbed largely unchanged and converted to natural folates in the liver Lower doses are converted to 5-MTHF during absorption through the intestine

About 60–90 µg of folate enters the bile each day and is excreted into the small intestine Loss of this folate, together with the folate of sloughed intestinal cells, accelerates the speed with which folate deficiency develops in malabsorption conditions

Transport

Folate is transported in plasma; about one-third is loosely bound to albumin and two-thirds unbound In all body fluids (plasma, cerebrospinal fluid, milk, bile)

folate is largely, if not entirely, 5-MTHF in the monoglutamate form Two types of folate-binding protein are involved in entry of MTHF into cells A high-affinity folate receptor takes folate into cells by endocytosis, is internalized by clathrin-coated pits or in a vesicle (caveola), which is then acidified, releasing folate Folate is then carried by the membrane folate transporter into the cytoplasm The high-affinity receptor is attached to the outer surface of the cell membrane by glycosyl phosphatidylinositol linkages It may be involved in transport of oxidized folates and folate breakdown products to the liver for excretion in bile An independent low-affinity reduced-folate carrier also mediates uptake of physiologic folates into cells but also of methotrexate

Biochemical Functions

Folates (as the intracellular polyglutamate derivatives) act as coenzymes in the transfer of single-carbon units (Fig 100-1 and Table 100-2) Two of these reactions are involved in purine and one in pyrimidine synthesis necessary for DNA and RNA replication Folate is also a coenzyme for methionine synthesis, in which methylcobalamin is also involved and in which THF is regenerated THF is the acceptor of single carbon units newly entering the active pool via conversion

of serine to glycine Methionine, the other product of the methionine synthase

reaction, is the precursor for S-adenosylmethionine (SAM), the universal methyl

donor involved in >100 methyltransferase reactions (Fig 100-1)

Figure 100-1

The role of folates in DNA synthesis and in formation on

S-adenosylmethionine (SAM), which is involved in numerous methylation reactions

[Reprinted from Hoffbrand AV et al (eds), Postgraduate Haematology, 5th ed, Blackwell Publishing, Oxford, UK 2005; with permission.]

During thymidylate synthesis, 5,10-methylene-THF is oxidized to DHF (dihydrofolate) The enzyme DHF reductase converts this to THF The drugs methotrexate, pyrimethamine, and (mainly in bacteria) trimethoprim inhibit DHF reductase and so prevent formation of active THF coenzymes from DHF A small

fraction of the folate coenzyme is not recycled during thymidylate synthesis but is degraded