Glicólise

Passos 1–5: 1.ª Metade da Glicólise

A 1.ª metade da glicólise requer um investimento energético de 2 moléculas de adenosina trifosfato (ATP) e serve para converter a glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance hexagonal em 2 trioses. O processo consiste em 5 etapas:

1. Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance → glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance 6-fosfato (G6P)
   • A hexocinase (HK) transfere um grupo fosforil do ATP para o 6.º carbono da glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance para formar G6P.
     • Requer magnésio (Mg²⁺) como cofator
     • Requer ATP
   • No fígado, esta etapa é catalisada pela glucocinase (uma enzima com a mesma função, mas com menor afinidade para a glucose), ajudando o fígado a servir de “tampão” para a glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance no sangue.
2. G6P → frutose-6-fosfato ( F6P F6P Glycolysis)
   • A fosfoglucose isomerase ( PGI PGI An aldose-ketose isomerase that catalyzes the reversible interconversion of glucose 6-phosphate and fructose 6-phosphate. In prokaryotic and eukaryotic organisms it plays an essential role in glycolytic and gluconeogenic pathways. In mammalian systems the enzyme is found in the cytoplasm and as a secreted protein. This secreted form of glucose-6-phosphate isomerase has been referred to as autocrine motility factor or neuroleukin, and acts as a cytokine which binds to the autocrine motility factor receptor. Deficiency of the enzyme in humans is an autosomal recessive trait, which results in congenital nonspherocytic hemolytic anemia. Glycolysis) converte G6P em F6P F6P Glycolysis.
   • Isomeriza a glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance aldose Aldose Basics of Carbohydrates a uma frutose cetose
3. F6P F6P Glycolysis → frutose-1,6-bifosfato ( FBP FBP Glycolysis)
   • A fosfofrutocinase (PFK-1) fosforila F6P F6P Glycolysis em C1, produzindo FBP FBP Glycolysis.
   • Requer Mg²⁺ como cofator
   • Requer ATP
   • Esta é uma reação limitante na glicólise e é, portanto, uma etapa regulada
4. FBP FBP Glycolysis → gliceraldeído 3-fosfato (GAP) + dihidroxiacetona fosfato (DHAP)
   • A aldolase Aldolase Becker Muscular Dystrophy corta o FBP FBP Glycolysis de 6 carbonos em 2 moléculas diferentes de 3 carbonos, GAP e DHAP.
   • A reação é uma clivagem de aldol com um intermediário enolato estabilizado por ressonância.
5. DHAP → GAP
   • A triose-fosfato isomerase (TIM) converte o DHAP e o GAP para permitir que o DHAP prossiga através da glicólise.

Passos 6–10: 2.ª Metade de Glicólise

A segunda metade da glicólise converte a triose GAP em piruvato, com a geração concomitante de 4 ATP e 2 nicotinamida adenina dinucleótido hidreto (NADH) por cada 2 GAP. Assim, o investimento energético dos passos 1–5 é pago duas vezes aqui. Em certos tipos de células e condições, estes 5 passos são a fonte predominante de ATP:

6. GAP → 1,3-bisfosfoglicerato ( 1,3-BPG 1,3-BPG Glycolysis)
   • A gliceraldeído-3-fosfato desidrogenase (GAPDH) catalisa a fosforilação e a oxidação de GAP, produzindo 1,3-bifosfoglicerato ( 1,3-BPG 1,3-BPG Glycolysis).
   • O 1,3-BPG 1,3-BPG Glycolysis é o 1.º intermediário de alta energia na glicólise.
   • Produz 2 NADH a partir de nicotinamida adenina dinucleótido( NAD NAD+ A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway⁺) e um ião fosfato (Pi)
     • Em condições aeróbicas, a oxidação do NADH na cadeia respiratória regenera o NAD NAD+ A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway⁺e produz ATP adicional.
     • Sob condições anaeróbicas, são necessárias reações adicionais para regenerar o NAD NAD+ A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway⁺.
7. 1,3-BPG 1,3-BPG Glycolysis → 3-fosfoglicerato
   • A fosfoglicerato cinase (PGK) converte 1,3-BPG 1,3-BPG Glycolysis em 3-fosfoglicerato (3PG).
   • Requer Mg²⁺ como cofator
   • Produz ATP
   • As reações das GAPDH e PGK são acopladas para permitir que a reação energética desfavorável da GAPDH seja “levada para a frente” pela reação altamente favorável PGK.
8. 3PG → 2-fosfoglicerato
   • A fosfoglicarato mutase (PGM) converte 3PG em 2PG, transferindo o fosfato do grupo funcional do C3 para o C2.
   • Gera um complexo 2,3-bisfosfoglicerato (2,3-BPG)–enzima
9. 2PG → fosfoenolpiruvato ( PEP PEP A monocarboxylic acid anion derived from selective deprotonation of the carboxy group of phosphoenolpyruvic acid. It is a metabolic intermediate in glycolysis; gluconeogenesis; and other pathways. Glycolysis)
   • A enolase Enolase A hydro-lyase that catalyzes the dehydration of 2-phosphoglycerate to form phosphoenolpyruvate. Several different isoforms of this enzyme exist, each with its own tissue specificity. Glycolysis desidrata o 2PG a fosfenoenolpiruvato ( PEP PEP A monocarboxylic acid anion derived from selective deprotonation of the carboxy group of phosphoenolpyruvic acid. It is a metabolic intermediate in glycolysis; gluconeogenesis; and other pathways. Glycolysis).
   • O PEP PEP A monocarboxylic acid anion derived from selective deprotonation of the carboxy group of phosphoenolpyruvic acid. It is a metabolic intermediate in glycolysis; gluconeogenesis; and other pathways. Glycolysis é o 2.º intermediário de alta energia formado na glicólise.
10. PEP PEP A monocarboxylic acid anion derived from selective deprotonation of the carboxy group of phosphoenolpyruvic acid. It is a metabolic intermediate in glycolysis; gluconeogenesis; and other pathways. Glycolysis → piruvato
    • A piruvato cinase (PK) converte PEP PEP A monocarboxylic acid anion derived from selective deprotonation of the carboxy group of phosphoenolpyruvic acid. It is a metabolic intermediate in glycolysis; gluconeogenesis; and other pathways. Glycolysis em pyruvate Pyruvate Derivatives of pyruvic acid, including its salts and esters. Glycolysis (Pyr), libertando uma grande quantidade de energia, utilizada para impulsionar a síntese de ATP.
    • Produz ATP

Reacção líquida: glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance + 2 P_i + 2 ADP + 2 NAD NAD+ A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway⁺ → 2 piruvato + 2 ATP + 2 NADH + 2 H⁺ + 2 H₂O

Regulação da Glicólise

• A glicólise opera continuamente na maioria dos tecidos, com uma taxa variável de acordo com as necessidades da célula.
• Os fatores que induzem a glicólise inibem a gluconeogénese (o inverso da glicólise) e vice-versa, pois a gluconeogénese é regulada reciprocamente.
• A insulina e o glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions são as principais hormonas que controlam os fluxos da glicólise e da gluconeogénese.
• A regulação otimal da via é conseguida através do controlo das reações com uma grande alteração negativa da energia livre, das quais há 3 em glicólise.

Hexocinase (HK)

• Regula o passo 1 da via
• Negativamente regulado pelo excesso de G6P
• Não é relevante quando a glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance é derivada do glicogénio, já que a glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance é libertada do glicogénio como G6P

Fosfofrutocinase

• A PFK-1 é o ponto primário de controlo do fluxo da glicólise; regula a etapa 3
• A FBPase catalisa o passo inverso da PFK-1 na gluconeogénese, e ambas as enzimas são reguladas reciprocamente.
  • Quando a PFK-1 é inibida e a FBPase é ativada, o fluxo é deslocado da glicólise para a gluconeogénese.
• A PFK-1 é inibida pelo ATP alostericamente, um indicador de abundância de energia.
• A PFK-1 é ativada pela adenosina monofosfato (AMP) e pela adenosina difosfato (ADP) alostericamente, indicadores de escassez de energia.
• A PFK-1 é inibida pelo citrato alostericamente.
• A PFK-1 é fortemente ativada pela frutose-2,6-bifosfato (F2,6P) de forma alostérica.
  • A F2,6P tem o efeito oposto no passo oposto na gluconeogénese.
  • A F2,6P é sintetizada e degradada por uma enzima bifuncional chamada PFK-2/FBPase-2, cuja atividade é controlada por muitos efetores alostéricos e hormonas.
  • A F6P F6P Glycolysis promove a síntese de F2,6P, ativando a glicólise.
  • No estado alimentado: a insulina estimula a desfosforilação de PFK-2/FBPase-2 → aumentando os níveis de F2,6P → aumentando o fluxo glicolítico
• As catecolaminas (através do AMP cíclico) inibem as enzimas glicolíticas HK, PFK-1, PFK-2 (que produz a frutose 2,6 bifosfato) e PK.
  • Induz a síntese da piruvato carboxilase, da PEP PEP A monocarboxylic acid anion derived from selective deprotonation of the carboxy group of phosphoenolpyruvic acid. It is a metabolic intermediate in glycolysis; gluconeogenesis; and other pathways. Glycolysis carboxilase, da FBPase, e da G6Pase

Piruvato cinase (PK)

• Regula o passo 10 (último) da
• Ativado alostericamente pela FBP, indicando acumulação de intermediários glicolíticos a montante: resulta num “puxar” através do caminho glicolítico
• Alostericamente inibido por ATP, indicando uma fonte de energia abundante
• No fígado, alostericamente inibido pela alanina, um precursor da gluconeogénese

Relevância Clínica

• Galactosemia Galactosemia Galactosemia is a disorder caused by defects in galactose metabolism. Galactosemia is an inherited, autosomal-recessive condition, which results in inadequate galactose processing and high blood levels of monosaccharide. The rare disorder often presents in infants with symptoms of lethargy, nausea, vomiting, diarrhea, and jaundice. Galactosemia: metabolismo defeituoso do açúcar galactose Galactose An aldohexose that occurs naturally in the d-form in lactose, cerebrosides, gangliosides, and mucoproteins. Deficiency of galactosyl-1-phosphate uridyltransferase causes an error in galactose metabolism called galactosemia, resulting in elevations of galactose in the blood. Lactose Intolerance. As manifestações clínicas começam quando a alimentação do leite é iniciada. Os bebés desenvolvem letargia, icterícia, disfunção hepática progressiva, doença renal, cataratas, perda de peso e suscetibilidade a infeções bacterianas (especialmente E coli). Podem desenvolver incapacidade intelectual se a doença não for tratada. A base do tratamento é a exclusão da galactose Galactose An aldohexose that occurs naturally in the d-form in lactose, cerebrosides, gangliosides, and mucoproteins. Deficiency of galactosyl-1-phosphate uridyltransferase causes an error in galactose metabolism called galactosemia, resulting in elevations of galactose in the blood. Lactose Intolerance da alimentação.
• Intolerância hereditária à frutose: deficiência de frutose-1-fosfato aldolase Aldolase Becker Muscular Dystrophy. Os sintomas começam após a ingestão de frutose (açúcar da fruta) ou de sacarose, apresentando-se mais MAIS Androgen Insensitivity Syndrome tarde na vida. Apresenta-se com dificuldade em ganhar peso, vómitos, hipoglicemia, disfunção hepática e defeitos renais. As crianças com a doença não apresentam problemas se evitarem a frutose e a sacarose alimentar.
• Deficiência de frutose 1,6-difosfatase: associada a uma gluconeogénese deficiente. Os sintomas incluem hipoglicemia, intolerância ao jejum e hepatomegalia. Tratamento emergente de episódios hipoglicémicos com fluidos ricos em glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance por IV e a prevenção do jejum são os pilares da terapia. Casos graves podem requerer a suplementação com glicose para evitar a hipoglicemia.
• Doenças de armazenamento do glicogénio: deficiência de enzimas responsáveis pela degradação do glicogénio. Dependendo da enzima afetada, estas doenças podem afetar o fígado, os músculos ou ambos. Existem várias doenças clinicamente significativas do armazenamento de glicogénio com diferentes apresentações.
• Deficiência de glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance 6-fosfato desidrogenase ( G6PD G6PD Pentose Phosphate Pathway): doença genética que ocorre quase exclusivamente no sexo masculino e afeta principalmente os glóbulos vermelhos, causando hemólise e anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types hemolítica. Os sintomas incluem dispneia, fadiga, taquicardia, urina escura, palor e icterícia. A anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types hemolítica pode ser desencadeada por infeções, certos medicamentos (antibióticos, antimaláricos) e após a ingestão de favas.

De seguida estão apresentadas enzimas da via da glicólise que podem estar envolvidas em defeitos enzimáticos congénitos:

• Deficiência de piruvato cinase ( mais MAIS Androgen Insensitivity Syndrome comum)
• Hexokinase Hexokinase An enzyme that catalyzes the conversion of ATP and a d-hexose to ADP and a d-hexose 6-phosphate. D-glucose, d-mannose, d-fructose, sorbitol, and d-glucosamine can act as acceptors; ITP and dATP can act as donors. The liver isoenzyme has sometimes been called glucokinase. Glycolysis de eritrócitos
• Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance fosfato isomerase
• Fosfofrutocinase

Estes defeitos enzimáticos congénitos produzem anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types hemolítica.

Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types hemolítica: grupo de anemias que se devem à destruição ou eliminação prematura de hemácias. Anomalias intrínsecas de hemácias levam à depuração esplénica (hemólise extravascular). A destruição crónica de hemácias pode-se apresentar como icterícia, esplenomegalia, colelitíase, hematúria e sintomas de anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types (falta de ar AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation, fadiga, síncope e taquicardia).