Introduction

Betaine, also known as glycine betaine and N,N,N trimethyl glycine, is an osmolyte found across animals, plants, and microorganisms. It is a zwitterionic amino acid derivative that can be endogenously produced by the oxidation of choline[1 ], and exogenously absorbed as a dietary nutrient. The name betaine comes from its discovery from beta vulgaris (beets) in the 1860s, but later it was found at high concentration in other dietary sources like wheat bran, spinach, and seafood[2-4 ]. In mammals, from the physiological point of view, betaine serves primarily two roles: as one of the major osmolytes accumulated in the tissues for cell volume regulation, mainly in kidney, and as a methyl donor for the toxic metabolite, homocysteine (Hcy), to convert it into methionine [1 ,4 ]. The daily betaine uptake in human diet ranges from 1-2.5g/day, based on individual consumption. The study on red blood cell physiology at high betaine doses showed mild perturbance and suggested safe daily betaine intake was 9-15g/day [2 ]. The active absorption of betaine across the enterocytes is thought to be via sodium/chloride dependent amino acid transport system (SLC36A1, SLC36A2), and also passive sodium independent [1 ,2 ,5 ,6 ]. A rapid adsorption and distribution up to 1-3mM within 1-2h of intake was recorded in human studies on betaine supplementation [2 ,7 ]. However, the tissue concentration for an osmolyte, as expected, is higher than plasma concentration [8 ]. Apart from diet and supplementation, betaine can be synthesized via a two-step irreversible process using choline in mitochondria (see figure 1). Firstly, the enzyme choline dehydrogenase oxidates choline into betaine aldehyde. And then, betaine aldehyde is converted to betaine by the same enzyme in the presence of nicotinamide adenine dinucleotide (NAD+). This betaine is catabolized via transmethylation reactions involved in vital biological processes [2 ]. This transmethylation is catalysed by betaine-homocysteine methyltransferase (BHMT), which detoxifies Hcy by converting it into methionine and producing S-adenosylmethionine (SAM).