Transport and cellular uptake

Blood circulation: Normai plasma concentrations ofTyrare around 66 p-mol/L (Anueh et ill., 1999). The amino acid enters cells from blood \ ia several transporters, including system T (TAT I) and I AT I, whose expression patterns vary considerably between specific tissues. LAT1 also transports D-pheny¡alanine (Vanagula el aL 2001). Blood-bram barrier The sodium-independent transporter TAT1 and the glvcoprotein-anchored exchangers LAT I and I AT2 in brain capillary endothelial cells are involved in Tyr transport, but their relative importance, location, and the role of other transporters is not completely understood. Tyr competes with other large neutral amino acids (valine, leucine, isoleucine. methionine, phenylalanine, tryptophan, and histidinc) for the trail-sport mechanisms from blood into the brain (Pietz el at., 1999). Matemo-fetal transfer; The exchanger LAT1 appears to be the major route for Tyr travelling from maternal blood into the syncytioirophoblast (Ritchie and Taylor, 2001). Transfer across the basolateral membrane may proceed predominantly via LAT1 and LAT2 (Ritchie and faylor. 2001): a contribution of TAT I. which is strongly expressed in placenta (Kim et al.,200\), has been disputed (Ritchie and Taylor. 2001).

L-Tyrosine

Tyrosine a mmol raus (erase (PLP)

4-Hydroxy-phenylpyruvate u-ketogl uta rate gl uta mate

O II

de hydro- Fe1 * ascorbale"* ■. * 4-hydroxypyruvate Y ¿¡oxygenase A (ferrous iron) ascorbate-' ^e3-

Homogentisate OH

dehydro- Fe2' ascoröaie"*v Homogentisate j 1,2-d ¡oxygenase A (ferrous iron) Fe3'

de hydro- Fe1 * ascorbale"* ■. * 4-hydroxypyruvate Y ¿¡oxygenase A (ferrous iron) ascorbate-' ^e3-

Homogentisate OH

C—COOH

ascorbate'

4-Maleyl-acetoacetate r^,

COOH

o^/JNc_cooh

Mai ey lacetoace late ¡some rase

4-Fumaryl-acetoacetate

COOH

Fumaryl acetoacetase

Fumarate

COOH

Fumarate

HOOC

Acetoacetate

Figur» 8.38 Metabolism of (.-tyrosine

Metabolism

Both mitochondrial and cytusolic forms of tyrosine aminotransferase (PLP-dependent; EC2.6.1.5) move the amino group from Tyr to alpha-ketoglutarate. Mitochondrial and cytosolic aspartate aminotransferase (AST; EC2.6.1.11 can also catalyze the same reaction. The mitochondrial AST. which contributes to Tyr metabolism especially in the small intestinal mucosa, can he generated by partial hydrolysis of aromatic amino acid transferase (EC2.6.1.57). The next step, oxidative decarboxylation to homogentisate. is facilitated by 4-hy droxy p heny I pyruvate dioxygenasc (ECI.13.11.27). Ascorbatc reverts the enzyme-bound iron to the ferrous state whenever it gets oxidized Vitamin C deficiency impairs Tyr catabolism and causes tyrosinemia. Homogentisate 1.2-d¡oxygenase (EC 1.13.11,51 is another ferroenzyme whose iron must be maintained by reduced aseorbate. Maleylacetoacetate isomerasc (EC5.2.1.2)catalyzes the next step. This enzyme is Afunctional, since it has also glutathione S-transferase (EC2.5.1 I St activity (GST zeta 1). Fumarylacetoacetase (EC3,7-I.2) completes the conversion of Tyr to acetoacetate and fumarate.

I ti ma rate can be utilized directly through the Krcbs cycle. Acetoacetate can be activated to acetyl-CoA through the successive actions of 3-oxoacid Co A-transferase (succtnyl-CoA transferase; EC 2.8.3.5) and acetyl-CoA C-acetyl transferase (thiolase; EC2.3.I.9). Depending on the redox potential it maj also be reduced to beta-hydroxybutyrate by NAD! f-dependent 3-hydroxybutyrate dehydrogenase (EC I. 1.1.30).

Storage

On average, the body contains 33 mgTyr per gram total protein (Smith, 1980). Amino acids are released as functional proteins are broken down during normal turnover. Accelerated protein catabolism occurs in response to starvation, severe trauma or infection.

Excretion

Due to very effective renal reabsonption of filtered Tyr very little is lost with urine. Uptake from the proximal tubular lumen uses mainly the sodium-dependent system B" (Avissar et til.. 2001), and is augmented by the action of the sodium-independent transporter complexes b'1'-rBAT and BATl-rBAT (Verrev el at., 1999). Impaired reabsorptton in I lartnup disease, possibly due to defective system B". causes excessiv e renal losses.

Normal daily excretion of breakdown products ofTyr-derived catecholamine, such as vanillylmandelic acid and homovanilhc acid, adds up to several milligrams.

Regulation

The rate ofTyr uptake into various tissues including brain appears to be governed largely by availability (as reflected by blood concentration) from dietary intake and endogenous synthesis from phenylalanine without significant intervening regulatory events (Garabal et ul.. 19X8). Oral contraceptives decrease Tyr availability during the luteal phase by promoting transamination i Yloller et al., 1995).

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