Fig 1.
Substrates are indicated by rectangular boxes, green in the methionine cycle and red in the folate cycle. Each black arrow represents a biochemical reaction and the blue and yellow ellipses on the arrows contain the acronyms of the enzymes that catalyze the reactions. The yellow ellipses indicate the enzymes that are up- or down-regulated in females (see Table 1). Each red arrow is a long-range allosteric influence, either activation (arrow) or inhibition (bar). Substrate abbreviations: Met, methionine; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; Hcy, homocysteine; 5mTHF, 5-methyltetrahydrofolate; THF, tetrahydrofolate; 10fTHF, 10-formyltetrahydrofolate; DHF, dihydrofolate; CH2-THF, 5,10-methylenetrahydrofolate; CH = THF, 5,10-methenyltetrahydrofolate; SphMY, sphingomyelin; PtEA, phosphotidylethanolamine; Cho, choline; Bet-Ald, betaine aldehyde; Bet, betaine. Enzyme abbreviations: AICAR(T), aminoimidazolecarboxamide ribonucleotide (transferase); FTD, 10-formyltetrahydrofolate dehydrogenase; FTS, 10-formyltetrahydrofolate synthase; MTCH, 5,10-methylenetetrahydrofolate cyclohydrolase; MTD, 5,10-methylenetetrahydrofolate dehydrogenase; MTHFR, 5,10-methylenetetrahydrofolate reductase; TS, thymidylate synthase; SHMT, serine hydroxymethyltransferase; PGT, phosphoribosyl glycinamidetransformalase; DHFR, dihydrofolate reductase; NE, nonenzymatic interconversion of THF and 5,10-CH2-THF; MAT-I,methionine adenosyl transferase I; MAT-III, methionine adenosyl transferase III; AMD1, adenosylmethionine decarboxylase; GNMT, glycine N-methyltransferase; AS3MT, arsenic methyltransferase; PEMT, phosphotidylethanolamine methyltransferase; GAMT, gunadino-acetate methyltransferase; DNMT, DNA-methyltransferase; SAHH, S-adenosylhomocysteine hydrolase; CBS, cystathionine β-synthase; MS, methionine synthase; SMS, sphingomyelin synthase; PhL-D, phospholipade D; ChOx, choline oxidase; BAH, betaine aldehyde dehydrogenase; BHMT, betaine-homocysteine methyltransferase.
Fig 2.
Hcy and E2 throughout the menstrual cycle.
Model predictions of relative Hcy variation using three different estradiol curves are plotted. (Panel A). The Hcy experimental data and the Hcy model curves are plotted relative to the Hcy concentration on day 14 (predicted ovulation) of the mean estradiol curve. The Hcy data [44] is plotted with error bars representing the standard deviation. The model estradiol curves were determined by interpolation of data from [7, 42, 43]. The data is regraphed in Panel B, where the three curves are mean estradiol (Mean), the 95th percentile (Upper), and the 5th percentile (Lower). The errors bars are standard deviation. The corresponding model Hcy curve for each estradiol curve is plotted in Panel A in the same color with the same label.
Table 1.
Homocysteine and the contraceptive pill in the mathematical model.
Fig 3.
One-carbon metabolism during the menstrual cycle.
Panel A shows the model concentrations of Met, SAM, SAH, and Hcy and the SAM/SAH ratio throughout the menstrual cycle, relative to their values at the beginning of the cycle. Panel B shows the model velocities of the MS, CBS, and AMD1 reactions, and the fraction of flux arriving from SAH that is transsulfurated. Panel C shows the model velocities of four important methyltransferases, GNMT, GAMT, DNMT, and PEMT. Finally, Panel D shows the relative model concentrations of 5mTHF and GSH, and the velocities of the TS and AICART reactions.
Fig 4.
NHANES data on Hcy and vitamin deficiencies.
These scatterplots lump together the NHANES studies for 2001–2006. Data is for men and women between ages 20 and 40. The red dotted curves show the mean Hcy concentration of vitamin bins of small size. RBC folate and B6 are in nanomolar, B12 is in picomolar, and plasma Hcy is in micromolar. RBC folate stands for red blood cell folate.
Table 2.
The effects of B12 deficiency in males and females in the model.
Fig 5.
Effects of folate deficiency in the mathematical model.
For both males and females, vMS, the velocity of the MS reaction, is homeostatic until total folate gets below 30% of normal. As a result, the Hcy concentration does not depend strongly on total folate. As discussed in [12], the Vmax of the MS reaction is larger in females than in males, and as usual, the female Hcy concentration is below the male Hcy concentration. Both Hcy curves show the convex shape of the mean curves in the NHANES data in Fig 4a and 4b.
Fig 6.
Homocysteine throughout pregnancy.
Estradiol (E2) increases significantly from about 0.35 nM to 58.46 nM throughout pregnancy [7, 11]. The E2 data from [11] is reproduced in Panel B. Our model predicts Hcy throughout pregnancy as a result of E2 changes. Hcy is plotted relative to its concentration in menstruating women (red curve, Panel A). Our model corresponds well with data from [52], which is also plotted relative to Hcy in menstruating women (black dots, Panel A). The black bars indicate standard deviation.