Megoblastic Anemia Flashcards
what is seen on a blood smear in a person with megoblastic anemia?
- erythrocytes that are either
- normochromatic
- and either
- normal, or
- VERY LARGE & misshapen (often oval)
- PMNs with hyper-segmented nuclei
what is the general pathophysiology of megoblastic anemia?
-
impaired DNA synthesis → reduction of nuclear divisions during erythroblast maturation → abnormally large RBCs
- DNA synthesis is impaired d/t a defect in the transfer of one carbon groups, which depends on the formation of a one carbon pool. an insufficient one carbon pool is usually d/t
- folate deficiency
- Vit B deficiency
- DNA synthesis is impaired d/t a defect in the transfer of one carbon groups, which depends on the formation of a one carbon pool. an insufficient one carbon pool is usually d/t
what are the general steps / molecules required for the for the formation of the the carbon pool?
- the one carbon pool consists of a tetrahydrofolate group (FH4) that carries a carbon unit in either a formyl, methylene, or methyl form.
- FH4 comes from FH4 synthesis, which requires:
- folate
- dihydrofolate reductase
- NADPH
- the carbon unit is donated from either:
- amino acids - glycine, serine, histidine
- formaldehyde / formate
- FH4 comes from FH4 synthesis, which requires:
describe the structure of folate.
overall: pteridine ring + PABA (p-aminobenzoic acid) + glutamate(s)
- two forms:
- ingested form: has several glutamates
- absorbed form: has single glutamate (mono-form)
tetrahydrofolate synthesis
- requires what molecules?
- involves what steps?
- requires:
- folate
- DHFR (dihydrofolate reductase)
- 2 NADPH
- steps:
- ingestion of folate
- removal of extra glutamates in intestine
- absorption of mono-form (pteridine ring+ PABA + single glutamate)
- conversion of folate (F) → FH4
- F reduced to FH2 by DHFR and NADPH
- FH2 reduced to FH4 by DHFR and NADPH
what are the sources of one-carbon units that are carried by FH4 in the carbon pool?
- glycine
- serine
- histidine
- formaldehyde
- formate
attachment of the one-carbon unit to FH4
- requires what molecules?
- involves what steps?
- yields what forms of transferrable carbon?
three forms of carbon unit in carbon pool: formyl, methylene, methyl. they are synthesized in the following steps:
-
FH4 → N10-formyl-FH4: requires ATP
- carbon attached in the form of a “formate” group to 10th nitrogen of FH4
- N10-formyl-FH4 → N5,N10-methylene-FH4: requires NADPH
- N5,N10-methylene-FH4 → N5-methyl-FH4: requires NADH
generation of what FH4-cabon product is the “least” reversible? why?
-
N5-methyl-FH4 (synthesized from N5,N10-methyelene-FH4 using NADH)
- the “methyl” form of carbon is CH3, and is thus as reduced as possible.
- thus, N5-methyl-FH4 must donate its methyl group or stay methylated)
what cellular processes require donation from the one-carbon pool? which form form of FH4 serves as the donor in each case?
- purine biosynthesis - formyl form
- dTMP synthesis - methylene form
- SAM reactions - methyl form
purine biosynthesis requires carbon donation from what form of FH4?
formyl form: N10-formyl-FH4
SAM (S-adenosyl methionine) reactions require carbon donation from what form of FH4?
methyl form: N5-methyl-FH4
dTMP synthesis
methylene form: N5,N10-methyl-FH4
what are the roles of NADPH in one-carbon unit transfer?
- generation of FH4: used 2x by DHFR to reduce folate → FH2 → FH4
- generation of N5,N10-methylene-FH4 (used in dTMP synthesis) from N10-formyl-FH4
describe the structure of Vitamin B12.
= corrin ring + long chain + 3rd group
- corrin ring
- has cobalt in the center
- resembles heme
- 3rd group is one of the following:
- methyl
- adenosyl
- cyanyl forms
outline the absorption of Vitamin B12
Vit B12 consumed in protein rich dietary sources, then moved into the blood by several steps:
- Vit B12-protein carrier complex enters stomach
- here, the protein carrier is denatured, after which Vit B12 immediately becomes bound by other carriers:
- initially - bound by R-binders made by gastric mucosa
- this is brief, as R-binders are quickly degraded by acid
- next - bound by intrinsic factor made by parietal cells
- initially - bound by R-binders made by gastric mucosa
- Vit-B-intrinsic factor complex travels all the way to the ileum, where it:
- is absorbed into the blood through ileal enterocytes, then
- attached to transcobalamin-II, which transports it to
- liver for storage
- other tissues for use
what is the role of Vit B12 in regeneration of SAM?
- Vit B joins N5-methyl-THF to form methyl-cobalamin, a group which can donate the methyl group to homocysteine to produce methionine + THF
- methionine → SAM → methylation of various molecules
what is the role of Vit B12 in the conversion of metabolic products into succinyl CoA? why is this important?
- Vit B joins methymalonyl CoA - a by product of 1. ketogenic metabolism and 2. odd-chain FA metobolism - allowing its conversion to succinyl-CoA
- thus, allowing its entry into the TCA cycle
SAM
- what molecules / steps are necessary for the generation of SAM?
- what is this importance of the SAM pathway?
- SAM synthesis
-
requires
- N5-methyl-FH4
- Vit B12
-
steps
- N5-methyl-FH4 bound by Vit B12
- this enables N5-methyl-FH4 to donate its methyl group to homocysteine, forming → methionine + THF
- THF: recycled into carbon pool for re-use
- methionine: converted to S-adenosyl methionine (SAM) by ATP
-
requires
- importance of SAM pathway:
- SAM methylatation is required for the production of several molecules, such as:
- EPI
- creatinine
- methylated nucleotides
- phosphatidyl choline
- melatonin
- serves to regenerate THF
- SAM methylatation is required for the production of several molecules, such as:
what does homocysteine come from?
how is homocysteine metabolized?
- homocysteine comes from a SAM molecule that has donated its methyl group
- homocysteine then processed in one of two ways:
- converted into methionine for regeneration of SAM. requires
- N5-methyl-THF
- Vit B12
- converted ty cystathionine → cysteine. requires
- Vit B6
- converted into methionine for regeneration of SAM. requires
what leads to hyper-homocysteinemia? explain.
- accumulation of homocysteine, due to either
- impaired conversion to methionine
- folate deficiency
- Vit B12 deficiency
- impaired conversion to cystathionine
- Vit B6 deficiency
- impaired conversion to methionine
what is the “alternative pathway to methionine”? what is required for this pathway?
- a pathway (in the liver) that can partially mitigate hyper-homocysteinemia by converting homocysteine to methionine
- requires: choline
- choline → betaine
- betaine donates a methyl group to homocysteine, restoring methionine
what biochemical pathways can somewhat mitigate hyper-homocysteinemia due to Vit B12 deficiency? what is the caveat of each?
- conversion of homocysteine → cystathione
- this works temporarily, eventually cysteine accumulates & inhibits cystathione generation by neg feedback
- conversion of homocysteine → methionine by betaine (choline)
- this only pathway only works in the liver. it does NOT stop the neurological affects of hyper-homocysteinemia
what clinical features would help dx folate-deficient megoblastic anemia (vs Vit B12 megoblastic anemia?)
- presentation
- folate deficiency, during pregnancy, can also lead to several fetal defects:
- neural tube defects
- spina bifida
- anencephaly
- folate deficiency, during pregnancy, can also lead to several fetal defects:
- dx
- increased FIGLU levels (histidine metabolite)
methotrexate
- what is its role?
- how does it work?
- used in tx of cancer
-
inhibits dTMP synthesis by interfering with one-carbon transfer:
- blocks DHFR → no conversion of FH2 to FH4 → no N5,N10=methylene-FH4
5-FU
- what is its role?
- how does it work?
used in the tx of cancer
- used in the tx of cancer
- inhibits synthesis of dTMP
- by serving as an analog of uracil (F-dUMP) blocking dUMP → dTMP
