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This review discusses the epidemiology, pathophysiology, genetic etiology, and management of phenylketonuria (PKU). PKU, an autosomal recessive disease, is an inborn error of phenylalanine (Phe) metabolism caused by pathogenic variants in the phenylalanine hydroxylase ( PAH ) gene. The prevalence of PKU varies widely among ethnicities and geographic regions, affecting approximately 1 in 24,000 individuals worldwide. Deficiency in the PAH enzyme or, in rare cases, the cofactor tetrahydrobiopterin results in high blood Phe concentrations, causing brain dysfunction. Untreated PKU, also known as PAH deficiency, results in severe and irreversible intellectual disability, epilepsy, behavioral disorders, and clinical features such as acquired microcephaly, seizures, psychological signs, and generalized hypopigmentation of skin (including hair and eyes). Severe phenotypes are classic PKU, and less severe forms of PAH deficiency are moderate PKU, mild PKU, mild hyperphenylalaninaemia (HPA), or benign HPA. Early diagnosis and intervention must start shortly after birth to prevent major cognitive and neurological effects. Dietary treatment, including natural protein restriction and Phe-free supplements, must be used to maintain blood Phe concentrations of 120–360 μmol/L throughout the life span. Additional treatments include the casein glycomacropeptide (GMP), which contains very limited aromatic amino acids and may improve immunological function, and large neutral amino acid (LNAA) supplementation to prevent plasma Phe transport into the brain. The synthetic BH4 analog, sapropterin hydrochloride (i.e., Kuvan®, BioMarin), is another potential treatment that activates residual PAH, thus decreasing Phe concentrations in the blood of PKU patients. Moreover, daily subcutaneous injection of pegylated Phe ammonia-lyase (i.e., pegvaliase; PALYNZIQ®, BioMarin) has promised gene therapy in recent clinical trials, and mRNA approaches are also being studied.

Phenylalanine ammonia-lyase (PAL) is the first enzyme of the general phenylpropanoid pathway catalyzing the nonoxidative elimination of ammonia from L-phenylalanine to give trans-cinnamate. In monocots, PAL also displays tyrosine ammonia lyase (TAL) activity, leading to the formation of p-coumaric acid. The catalytic mechanism and substrate specificity of a major PAL from sorghum (Sorghum bicolor; SbPAL1), a strategic plant for bioenergy production, were deduced from crystal structures, molecular docking, site-directed mutagenesis, and kinetic and thermodynamic analyses. This first crystal structure of a monocotyledonous PAL displayed a unique conformation in its flexible inner loop of the 4-methylidene-imidazole-5-one (MIO) domain compared with that of dicotyledonous plants. The side chain of histidine-123 in the MIO domain dictated the distance between the catalytic MIO prosthetic group created from ¹⁸⁹Ala-Ser-Gly¹⁹¹ residues and the bound L-phenylalanine and L-tyrosine, conferring the deamination reaction through either the Friedel-Crafts or E₂ reaction mechanism. Several recombinant mutant SbPAL1 enzymes were generated via structure-guided mutagenesis, one of which, H123F-SbPAL1, has 6.2 times greater PAL activity without significant TAL activity. Additional PAL isozymes of sorghum were characterized and categorized into three groups. Taken together, this approach identified critical residues and explained substrate preferences among PAL isozymes in sorghum and other monocots, which can serve as the basis for the engineering of plants with enhanced biomass conversion properties, disease resistance, or nutritional quality.

In two randomized trials, eluxadoline was more effective than placebo in reducing abdominal pain and improving stool consistency in patients who had irritable bowel syndrome with diarrhea. Pancreatitis developed in 5 of 1666 patients (0.3%) who received eluxadoline. The irritable bowel syndrome (IBS) with diarrhea is a common functional gastrointestinal disorder that is characterized by recurring abdominal pain, bloating, and loose, frequent stools in the absence of structural, inflammatory, or biochemical abnormalities. IBS with diarrhea is associated with impairment in health-related quality of life, places a considerable financial burden on society because of reduced work productivity, and increases the use of health-related resources. 1 , 2 IBS is the most frequent diagnosis in gastroenterology practices and one of the most frequent diagnoses in primary care practices. 3 Current treatment options for IBS with diarrhea are limited. Initial therapies include dietary and . . .

Telotristat ethyl (Xermelo ® ), a first-in-class peripheral tryptophan hydroxylase (TPH) inhibitor, is approved to treat carcinoid syndrome diarrhoea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy alone. Some neuroendocrine tumours secrete serotonin (5-HT) into the blood, resulting in frequent bowel movements (BMs) and other symptoms. Telotristat ethyl inhibits TPH, thereby reducing the production of 5-HT and improving carcinoid syndrome diarrhoea. In the 12-week placebo-controlled phase of randomized trials in patients with carcinoid syndrome diarrhoea (most of whom were receiving SSA therapy), the addition of oral telotristat ethyl 250 three times daily provided significant reductions in the frequency of BMs and levels of urinary 5-hydroxyindolacetic acid (u5-HIAA; a metabolite of 5-HT) relative to placebo. Telotristat ethyl 250 mg three times daily was well tolerated, with the proportion of patients reporting at least one treatment-emergent adverse event being similar to that with placebo. With regard to adverse events of special interest, relative to placebo, telotristat ethyl had a comparable incidence of depression-related symptoms, a somewhat higher incidence of gastrointestinal (GI) disorders and a higher incidence of elevated hepatic enzyme levels.

Exercise confers protection against obesity, type 2 diabetes and other cardiometabolic diseases 1 – 5 . However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity remain unclear 6 . Here we show that exercise stimulates the production of N -lactoyl-phenylalanine (Lac-Phe), a blood-borne signalling metabolite that suppresses feeding and obesity. The biosynthesis of Lac-Phe from lactate and phenylalanine occurs in CNDP2 + cells, including macrophages, monocytes and other immune and epithelial cells localized to diverse organs. In diet-induced obese mice, pharmacological-mediated increases in Lac-Phe reduces food intake without affecting movement or energy expenditure. Chronic administration of Lac-Phe decreases adiposity and body weight and improves glucose homeostasis. Conversely, genetic ablation of Lac-Phe biosynthesis in mice increases food intake and obesity following exercise training. Last, large activity-inducible increases in circulating Lac-Phe are also observed in humans and racehorses, establishing this metabolite as a molecular effector associated with physical activity across multiple activity modalities and mammalian species. These data define a conserved exercise-inducible metabolite that controls food intake and influences systemic energy balance. A newly identified exercise-induced signalling metabolite—an amidated conjugate of lactate and phenylalanine—can reduce food intake and improve blood glucose homeostasis.

Among patients with impaired glucose tolerance, the short-acting insulin secretagogue nateglinide did not reduce the incidence of diabetes over the course of 5 years. Nateglinide also did not reduce the risk of cardiovascular events. Therefore, nateglinide does not have a place in the management of impaired glucose tolerance. Among patients with impaired glucose tolerance, the short-acting insulin secretagogue nateglinide did not reduce the incidence of diabetes over the course of 5 years. Nateglinide also did not reduce the risk of cardiovascular events. Persons with impaired glucose tolerance are at increased risk for type 2 diabetes mellitus and cardiovascular disease 1 – 3 ; therefore, treatments that might reduce the incidence of diabetes and associated cardiovascular disease and death are potentially important. 3 The risk of diabetes is reduced with lifestyle interventions that involve increasing physical activity and reducing weight 4 – 6 and with metformin, 6 acarbose, 7 or rosiglitazone 8 therapy, but no trials to date have been powered to consider cardiovascular outcomes. Among persons with type 2 diabetes, reducing glycemia results in a small reduction in the risk of major macrovascular events. 9 Glucose levels after a glucose challenge, . . .

Brown planthopper (BPH) is one of the most destructive insects affecting rice (Oryza sativa L.) production. Phenylalanine ammonialyase (PAL) is a key enzyme involved in plant defense against pathogens, but the role of PAL in insect resistance is still poorly understood. Here we show that expression of the majority of PALs in rice is significantly induced by BPH feeding. Knockdown of OsPALs significantly reduces BPH resistance, whereas overexpression of OsPAL8 in a susceptible rice cultivar significantly enhances its BPH resistance. We found that OsPALs mediate resistance to BPH by regulating the biosynthesis and accumulation of salicylic acid and lignin. Furthermore, we show that expression of OsPAL6 and OsPAL8 in response to BPH attack is directly up-regulated by OsMYB30, an R2R3 MYB transcription factor. Taken together, our results demonstrate that the phenylpropanoid pathway plays an important role in BPH resistance response, and provide valuable targets for genetic improvement of BPH resistance in rice.

Metabolites resulting from the bacterial fermentation of dietary fibers, such as short-chain fatty acids, especially butyrate, play important roles in maintaining gut health and regulating various biological effects in the skin. However, butyrate is underutilized due to its unpleasant odor. To circumvent this organoleptic unfavorable property, phenylalanine butyramide (PBA), a butyrate precursor, has been synthesized and is currently available on the market. We evaluated the inhibition of mushroom tyrosinase by butyrate and PBA through in vitro assays, finding IC50 values of 34.7 mM and 120.3 mM, respectively. Docking calculations using a homology model of human tyrosinase identified a putative binding mode of PBA into the catalytic site. The anti-aging and anti-spot efficacy of topical PBA was evaluated in a randomized, double-blind, parallel-arm, placebo-controlled clinical trial involving 43 women affected by photo-damage. The results of this study showed that PBA significantly improved skin conditions compared to the placebo and was well tolerated. Specifically, PBA demonstrated strong skin depigmenting activity on both UV and brown spots (UV: −12.7% and −9.9%, Bs: −20.8% and −17.7% after 15 and 30 days, respectively, p < 0.001). Moreover, PBA brightened and lightened the skin (ITA°: +12% and 13% after 15 and 30 days, respectively, p < 0.001). Finally, PBA significantly improved skin elasticity (Ua/Uf: +12.4% and +32.3% after 15 and 30 days, respectively, p < 0.001) and firmness (Uf: −3.2% and −14.9% after 15 and 30 days, respectively, p < 0.01).

CRISPR–Cas-based genome editing holds great promise for targeting genetic disorders, including inborn errors of hepatocyte metabolism. Precise correction of disease-causing mutations in adult tissues in vivo, however, is challenging. It requires repair of Cas9-induced double-stranded DNA (dsDNA) breaks by homology-directed mechanisms, which are highly inefficient in nondividing cells. Here we corrected the disease phenotype of adult phenylalanine hydroxylase (Pah) enu2 mice, a model for the human autosomal recessive liver disease phenylketonuria (PKU) 1 , using recently developed CRISPR–Cas-associated base editors 2 – 4 . These systems enable conversion of C∙G to T∙A base pairs and vice versa, independent of dsDNA break formation and homology-directed repair (HDR). We engineered and validated an intein-split base editor, which allows splitting of the fusion protein into two parts, thereby circumventing the limited cargo capacity of adeno-associated virus (AAV) vectors. Intravenous injection of AAV-base editor systems resulted in Pah enu2 gene correction rates that restored physiological blood phenylalanine ( l -Phe) levels below 120 µmol/l [ 5 ]. We observed mRNA correction rates up to 63%, restoration of phenylalanine hydroxylase (PAH) enzyme activity, and reversion of the light fur phenotype in Pah enu2 mice. Our findings suggest that targeting genetic diseases in vivo using AAV-mediated delivery of base-editing agents is feasible, demonstrating potential for therapeutic application. AAV-mediated base editing corrects an autosomal recessive mutation in the Pah enu2 gene and ameliorates molecular deficits in a mouse model of metabolic liver disease.

In phenylketonuria (PKU) patients, a genetic defect in the enzyme phenylalanine hydroxylase (PAH) leads to elevated systemic phenylalanine (Phe), which can result in severe neurological impairment. As a treatment for PKU, Escherichia coli Nissle (EcN) strain SYNB1618 was developed under Synlogic’s Synthetic Biotic™ platform to degrade Phe from within the gastrointestinal (GI) tract. This clinical-stage engineered strain expresses the Phe-metabolizing enzyme phenylalanine ammonia lyase (PAL), catalyzing the deamination of Phe to the non-toxic product trans -cinnamate (TCA). In the present work, we generate a more potent EcN-based PKU strain through optimization of whole cell PAL activity, using biosensor-based high-throughput screening of mutant PAL libraries. A lead enzyme candidate from this screen is used in the construction of SYNB1934, a chromosomally integrated strain containing the additional Phe-metabolizing and biosafety features found in SYNB1618. Head-to-head, SYNB1934 demonstrates an approximate two-fold increase in in vivo PAL activity compared to SYNB1618. PKU patients have elevated phenylalanine levels which can result in neurological impairment. Here the authors utilize biosensor-based ultra-high-throughput screening to optimize PAL activity in a synthetic biotic platform for improved in vivo performance.