Endogenous sources

lnositol-3-phosphat« synthase (EC5-5.1.4), an NAD-containing enzyme, catalyzes the internal cyclization of glucose-6-phosphate to inositol-3-phosphate. After removal of the phosphate group by myo-inositol-l(or 4)-monophosphatase (EC3.1.3.25) the free form is released into circulation. About 4 g myo-inositol per day is formed in the kidneys.

Intestinal bacteria may also contribute to inositol supplies, but the amounts available from this source arc not know n.

Glucose-6-phosphate

Glucose-6-phosphate

1 D-myo-inositol-3-phosphate

Myo-inositol-1 (ord)-monophosphate se V.

OH OH

OH OH

1 D-myo-inositol

1 D-myo-inositol

Figure 10.SO Inositol synthesis

OjHjP ph2o, o3h2p ph2o3

I u L I o3Hsp PH2Oj

(phytate) PHsOa

OH O ^PHsOri

9 o Inositol pentaphosphate

1 (diverse isoforms)

03h2p phso3

Figure 10.SI Inositol poly-fihtisphact;,

Dietary sources

Average daily intake of free inositol, inositol monophosphate, and inositol phospholipids in the United Stales is about 1 g. mainly from meal, poultry, fish, and dairy products. Human milk contains about 180 mg/1 (Pereira el til.. 1990).

Distinct from these forms with high bioavailability are the inositol polyphosphates, and in particular phytate (inositol hexaphosphate, 1P6). Fhese forms are characteristic for plant-derived foods. Nuts and seeds are the richest sources, containing between 7 and 22mgg (poppy seeds 22 mg/g, pumpkin seeds 19mg/g, cashew and Brazil nuts about 18 mg/g, hazelnuts and sunflower seeds 16 mu g. pecans 15 mg/g, peanuts and walnuts Smggl. Grains and grain products are significant sources, especially when the whole grain is consumed (white bread cakes and other white flour products 2 mg/g, rye and other dark bread 3 mg/g). Many fruits, vegetables, and tubers also contribute (potatoes about I mg/g, apples, tomatoes, peas and cucumbers 0.2 -0.6tng/g). Brewed teas contain about 0.1 mg'mt (Siegenberg etal„ IVJl),

Digestion and absorption

The different forms of bioavailablc inositol, mainly free inositol and lipid-bound inositol, are absorbed w ith high efficiency from the small intestine.

Free myoinositol is taken up via the sodium-dependent myo-inositol transporter (SLC5A3) with high efficiency* Dietary inositol polyphosphates, including phytate UPfi). also reach circulation intact (Grases et al„ 2001). but are absorbed with only low efficiency and possibly through mechanisms thai do not involve the myo-inositol transporter. Phosphatidyl inositol, the main dietary source of inositol, can be hydroly/ed by pancreatic phospholipase A2. It is not clear how the lysophosphatide then enters the intestinal cell.

Contrary to earlier findings (Bitar and Reinhold, 1972), release of free inositol from dietary phytate is probably minimal, and most of this is mediated by phyiases already present in food. 3-Phytase (EC3.1.3.8, zinc-dependent), which is present in the small intestine of rats and other mammals, does not seem to be active in the human gut. A much smaller role, if any. is played by endogenous multiple inositol phosphate phosphatase (EC number not assigned) whieh is predominantly located in liver and kidney (Craxton et ai. 1997).

Some inositol from the higher inositol polyphosphates can be released by phytascs in plant foods during processing or storage prior to consumption. Food processing methods that release free inositol to some (often unpredictable) degree include germination. such as is used for malting (e.g. in beer production), fermentation, exposure to baker's yeasl, heating, and soaking (Sandberg ci ai, 1999).

Transport and cellular uptake

Blood circulation: Most inositol (typically about 29 p.mol/1) is present in blood in its free form; a much smaller amount is carried as phosphatidyl inositol in lipoproteins. Inositol concentrations depend partially on intake levels and decrease in the absence of significant intakes (Holub, I486). Plasma concentrations of phytate may be as high as 0.3 mg'l in response to dietary intakes (Grascs et ai, 2(X)i I.

lis sodium-dependent transporter (SLC5A3) mediates entry of free myo-inositol into cells in brain, kidneys, and other tissues. Inositol polyphosphates, including IP6, are also taken up into cells (Vuccnik and Shamsuddin, 1444). though the mechanism remains unclear.

Metabolism

Inositol phosphate interconversions: Tissues contain a wide range of inositol species with 0 to 6 phosphates attached. The enzymes, which add phosphate groups to specific intermediates, include myo-inositol 1-kinase (EC2.7.1.64), I-phosphatidyl inositol 4-kinase (EC2.7.1.67). lD-myo-inositol-trisphosphate 3-kinase (EC2.7.I.127), ID-myo-inositol-lrispbosphate 5-kinase (EC2.7.1.139), lD-myo-inositol-trisphosphate 6-kinase (EC2.7.1.133). ID-myo-inositol-teirakisphosphate l-kinase (EC2.7.1.134). and I D-myo-inositol-tetmkisphosphate 5-kinase (EC2.7.1.140).

Enzymes that remove phosphates from inositol polyphosphates include inositol-1,3,4,5-tetrakisphosphate3-phosphatase(EC3.1.3.62),inositol-1.4,5-trisphosphate I-phosphatase (EC3.1.3.61), i nos i toi -1,4,5-tri sph osphate 5-phosphatase (EC3.1.3.56), inositol-],4-bisphosphate 1-phosphatase (EC3.1.3.57), inositol-1.3-bisphosphate 3-phosphatasc ( EC3.1.3.65 ). inositol-1,4-bisphosphate I -phosphatase ( EC3.1.3.57), inositol-3.4-bisphosphate 4-phosphatase (EC3.I.3.66), and myo-inosiiol-l(or 4)-monophospbatase (EC3.1.3.25). Expression of these enzymes in different tissues is very diverse and in most cases under light control of regulators such as calmodulin. Phospholipids CDP-diacylglycerol-inositol 3-phosphat idyl transferase (EC2.7.8.111, a manganese-dependent microsomal enzyme, uses inositol and eytidine diphosphate-diacyiglycerol for the synthesis of phosphatidyl inositol. The complex synthesis

Inositol

Myo-inositol 1-{or 4)-monophosphatase

Myo-inositol""^ Hor4)-monophosphatase

Myo-inositol 1-kinase lnositOl-4-P

lnositol-3-P

lnositol-1-P

inosttoi-1.3-. btspnosphate / 3-phosphaiase ,.-'

lnositol-1,4-bisphosphate A -phosphatase

Inositol-1,4-tus phosphate 1 -phosphatase tHsphosphaie 4-phosphataa lnositol-1.4

Inositol-1.4

lnositol-3.4

lnositol-4,5

i Inositol-1.4,5- trisphosphale ln.-1,4,5- —tri sphosphale 1-phosphatase tnsphosph, " -—-__ J-phosphatase

lnositoi-1.3,4 Inositol-1.4,5

lnosttol-1,3.4,5- 3kir,asV leirakisphosphate / 3-phosphatase,.-",,--"'

I D-myo-inositol; trisphosphale^-," 6-kinase, /

1 D-myo-tnositOl'

tnsphosphate

5-kinase tnositoi-1.4.5.6

Inositol-1.3,4,6

tnositol-1.3.4.5

1D-myoinositol leirakisphosphate^ 1-kinase _ --

1 D-myo-inositol-

tetrakisphosphate

5-kinase lnosilot-1,3.4.5,6

Figure tO.SZ Inositol met.1 boltsm and breakdown of the various products and intermediates of inositol-containing phospholipids utilizes numerous enzymes, including phosphatidyl inositol 3-kinase (I C2.7.1.137). phosphatidylinositol 4-kinase (EC'2,7.1.67), I-phosphatidyl inositol-4-phosphate kinase (EC2.7.I.68), glycerophosphoinositol i nos itolphosphod¡esterase (EC3.1.4.43), 1,2-cyClic-inositol-phosphate phosphodiesterase (EC3.1.4.36), 1-phos-phatidy I inos i to I -4.5-bi sphosph ate phosphodiesterase (EC3.1.4.11), 1-phosphatidyli-nositol phosphodiesterase (EC3.1.4.I0), and others. Several of the intermediates serve as second messengers, including inositol-1,4.5-triphosphate and phosphatidyli-nositol-4.5-bisphosphate.

Catabolism. Iron-dependent myo-inositol oxygenase {EC 1.13.99. I) oxidizes inositol to D-glucuronate. which can be reduced by glucuronate reductase (ECI.I.1.19) to L-gufonate. Human glucuronate reductase may actually be identical with the NADP-dependent zinc-enzyme alcohol dehydrogenase (EC 1.1.1.2). Further metabolism of L-guIonate proceeds to 3-keto-L-gulonate (L-gulonatc 3-dehydrogenase:

tD-myo-lnosilOl

Oj HjO

Myo-inositol oxygenase (iron)

tD-myo-lnosilOl

O-Glucuronate

H-C-OH Glueuronate reductase

L-Guionate

NADPH NADP

L-Gulonate 3-dehydrogenase

NADP NADPH

H-C-OH L-Xylulose reductase

Xylito!

□ xylulose reductase

NADH

D-xylulose

ATP ADP

Xylutokinase (magnesium)

HjC I

Detiydro-L-gulonate decarboxylase

L-xylulose

OPHaOj

3-keto-L-gulonate

D-xyluiose-5-phosphate

Figur* 10.5.1 Inositol breakdown

ECI.1,1.45), L-xylulose (magnesium- or manganese-dependent dehydro-L-gulonate decarboxylase; EC4.1.1.34). xylitol (L-xylulose reductase; ECI. 1.1.10). D-xylulosc (manganese requiring D-xylulose reductase; ECI.1.1.9). and xylulose 5-phosphatC (magnesium-dependent xvlulokinase; EC2.7.1.17). Xylulose 5-phosphate is a normal intermediate of D-glucose metabolism via the pentose phosphate pathway and readily utilized, therefore.

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