Phenylalanine Ammonia Lyase in the Management of Phenylketonuria: The Relationship Between Ingested Cinnamate and Urinary Hippurate in Humans

Hoskins, J.A.; Gray, J.

doi:10.1016/s0022-5347(17)52987-0

Cited by 9 publications

(13 citation statements)

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“…PAL converts the excess systemic Phe to trans-cinnamic acid with trace amounts of ammonia (11,22). Trans-cinnamate has no embryotoxic effects in laboratory animals (10), and is converted in the liver to benzoic acid, which is excreted in the urine as hippurate (23). Small amounts of cinnamate and benzoic acid are also excreted (11).…”

Section: Discussionmentioning

confidence: 99%

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Preclinical evaluation of multiple species of PEGylated recombinant phenylalanine ammonia lyase for the treatment of phenylketonuria

Sarkissian

Gámez

Wan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

101

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Section: Discussionmentioning

confidence: 99%

“…Investigation of PAL treatment for PKU was initiated over two decades ago (10,11). When taken orally, in a nonabsorbable and protected form, PAL lowers plasma Phe concentration in rodent models of PKU (7,12,13) in short-term studies.…”

mentioning

confidence: 99%

Preclinical evaluation of multiple species of PEGylated recombinant phenylalanine ammonia lyase for the treatment of phenylketonuria

Sarkissian

Gámez

Wan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

101

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show abstract

“…Fourth, there are several lines of evidence suggesting that the product of the reaction, trans-cin namic acid, is harmless to man. It is metabolized by the liver to benzoic acid and is excreted in the urine mainly as hippuric acid [9,13]. Therefore, trans-cinnamic acid is a compound of very low toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, trans-cinnamic acid is a compound of very low toxicity. To date, no embryotoxicity in laboratory animals has been reported [9]. Ambrus et al [1] were unable to show any harmful effects of /ranx-cinnamic acid on mice given 25 mg/kg of this compound intravenously, a dose well above that expected to be produced by PKU individuals undergoing PAL reactor therapy [2], 7>a«x-cinnamic acid is known to inhibit PAL activity [8].…”

Section: Discussionmentioning

confidence: 99%

An Extracorporeal Hollow-Fiber Reactor for Phenylketonuria Using Immobilized Phenylalanine Ammonia Lyase

Larue¹,

Munnich²,

Charpentier³

et al. 1986

Dev Pharmacol Ther

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A hollow-fiber hemodialyzer with immobilized phenylalanine ammonia lyase was tested in vitro for depletion of blood phenylalanine in a recirculating system. A sustained reduction of phenylalanine was obtained in less than 1 h. The product of phenylalanine deamination, ?ra«5-cinnamicacid,isanontoxiccompound metabolized to benzoic acid by the liverandeliminatedintheurineashippuricacid.Asamodel.thisreactormayberelevantnotonly for the short-term management of hyperphenylalaninemia (particularly in pregnant phe- nylketonuric mothers), but for other metabolic diseases as well, provided that a biocatalyst effective on the accumulating substance is available.

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“…Recently, we reported on enzyme substitution therapy with the non-mammalian Phenylalanine Ammonia Lyase (PAL) [12, 13]. PAL, an enzyme which converts Phe into metabolically harmless trans -cinnamic acid and trace amounts of ammonia [14], empirically acts on the metabolic phenotype. The effect, which is independent of the PAH mutation’s influence on the corresponding protein, has the potential to correct all such forms of HPA.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of orally administered PEGylated phenylalanine ammonia lyase in mice for the treatment of Phenylketonuria

Sarkissian

Kang

Gámez

et al. 2011

Molecular Genetics and Metabolism

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Phenylketonuria (PKU), a Mendelian autosomal recessive phenotype (OMIM 261600), is an inborn error of metabolism causing impaired postnatal cognitive development in the absence of treatment. We used the Pahenu2/enu2 PKU mouse model to study oral enzyme substitution therapy with various chemically modified formulations of phenylalanine ammonia lyase (Av-p.C503S/p.C565S/p.F18A PAL). In vivo studies with the most therapeutically effective formulation (5 kDa PEG-Av-p.C503S/p.C565S/p.F18A PAL) revealed that this conjugate, given orally, yielded statistically significant (p = 0.0029) and therapeutically relevant reduction (~40%) in plasma phenylalanine (Phe) levels. Phe reduction occurred in a dose- and loading-dependent manner; sustained clinically and statistically significant reduction of plasma Phe levels was observed with a treatment ranging between 0.3 IU and 9 IU and with more frequent and smaller dosings. Oral PAL therapy could potentially serve as an adjunct therapy, perhaps with dietary treatment, and will work independently of phenylalanine hydroxylase (PAH), correcting such forms of hyperphenylalaninemias regardless of the PAH mutations carried by the patient.

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Phenylalanine Ammonia Lyase in the Management of Phenylketonuria: The Relationship Between Ingested Cinnamate and Urinary Hippurate in Humans

Cited by 9 publications

References 0 publications

Preclinical evaluation of multiple species of PEGylated recombinant phenylalanine ammonia lyase for the treatment of phenylketonuria

Preclinical evaluation of multiple species of PEGylated recombinant phenylalanine ammonia lyase for the treatment of phenylketonuria

An Extracorporeal Hollow-Fiber Reactor for Phenylketonuria Using Immobilized Phenylalanine Ammonia Lyase

Evaluation of orally administered PEGylated phenylalanine ammonia lyase in mice for the treatment of Phenylketonuria

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